Paediatric Respiratory Reviews 20 (2016) 3–9

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Paediatric Respiratory Reviews

Mini-Symposium: Ventilation Strategies in the Paediatric Intensive Care Unit

Ventilation strategies in paediatric inhalation injury Chong Tien Goh 1,*, Stephen Jacobe 2 1

Advanced Trainee in Intensive Care Medicine, Paediatric Intensive Care Unit, The Children’s Hospital at Westmead, Sydney Senior Staff Specialist, Paediatric Intensive Care Unit, The Children’s Hospital at Westmead, Sydney, and Clinical Associate Professor, Sydney Medical School, University of Sydney, NSW, Australia 2

EDUCATIONAL AIMS After reading this article the reader will be able to recognise:  the significance of inhalation injuries in children  ventilatory management strategies suitable for children with inhalation injuries  the potential role of additional pharmacological adjuncts that are sometimes used in inhalation injury

A R T I C L E I N F O

S U M M A R Y

Keywords: Inhalation injury Treatment Children

Inhalation injury increases morbidity and mortality in burns victims. While the diagnosis remains largely clinical, bronchoscopy is also helpful to diagnose and grade the severity of any injury. Inhalation injury results from direct thermal injury or chemical irritation of the respiratory tract, systemic toxicity from inhaled substances, or a combination of these factors. While endotracheal intubation is essential in cases where upper airway obstruction may occur, it has its own risks and should not be performed prophylactically in all cases of inhalation injury. The evidence-base informing the selection of optimal ventilation strategy in inhalation injury is sparse, and most recommendations are based on extrapolation from (largely adult) studies in acute respiratory distress syndrome (ARDS). Conventional ventilation using a lung-protective approach (i.e. low tidal volume, limited plateau pressure, and permissive hypercarbia) is recommended as the initial approach if invasive ventilation is required; various rescue strategies may become necessary if there is a poor response. The efficacy of many widely used pharmacologic adjuncts in inhalation injury remains uncertain. Further research is urgently required to address these gaps in our knowledge. Crown Copyright ß 2015 Published by Elsevier Ltd. All rights reserved.

INTRODUCTION Approximately 10-30% of patients hospitalised with burn injury have a concomitant inhalation injury, and inhalation injury is a significant risk factor for increased mortality and morbidity in adult and paediatric burns patients [1–8]. A recent large series of 850 children with inhalation injury admitted to a Shriners Children’s Hospital in the U.S.A. over a 10-year period found these children required mechanical ventilation

* Corresponding author. Paediatric Intensive Care Unit, The Children’s Hospital at Westmead, Locked Bag 4001, Westmead NSW 2145 Australia. E-mail address: [email protected] (C.T. Goh). http://dx.doi.org/10.1016/j.prrv.2015.10.005 1526-0542/Crown Copyright ß 2015 Published by Elsevier Ltd. All rights reserved.

for a mean of 15.2 days and the overall mortality rate was approximately 16%, with most deaths due to pulmonary dysfunction [9]. Mortality was significantly related to the size and depth of the burn. Inhalation injury increases the risk for pneumonia, and the contributions of inhalation injury and pneumonia to mortality are independent and additive [6]. A recent meta-analysis found the risk of death doubled with inhalational injury (13.9% vs 27.6%) [5]. While inhalation injury is associated with increased morbidity in the acute phase, a study of paediatric burn survivors found it did not affect long-term quality of life [10]. Unfortunately, a universally recognised definition of inhalation injury is currently lacking, and specific evidence-based treatment options are largely lacking.

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The lung injury seen following inhalation associated with burns results from direct thermal injury to the airways, local chemical irritation to the respiratory tract, or systemic toxicity due to inhalation of carbon monoxide, cyanide, or other toxins [11]. In addition, the systemic inflammatory response to burns, sepsis, pneumonia, and ventilator-induced lung injury (VILI) may contribute to additional lung injury. Inhalation injury may often be associated with pneumonia and ARDS, however burn victims without inhalation injury can also develop these, and it should not be assumed that the presence of pulmonary complications signifies that an inhalation injury has been sustained. While some studies found patients with inhalation injury required increased fluid volume for resuscitation compared to those without [12,13], others have not confirmed this [14]. Unlike damaged skin that can be dressed and grafted, the management of inhalation injury is mainly supportive, with care taken to protect the lung from secondary injury. This review will focus on the respiratory support strategies, and in particular, ventilation strategies, for children with inhalation injuries. PATHOPHYSIOLOGY Inhalation injury can cause damage by a combination of: 1) direct thermal damage to the upper airways; 2) local chemical irritation of the respiratory tract, and; 3) systemic toxicity due to inhalation of toxic substances. Lee et al. [15] recently reviewed this topic. Direct thermal damage to upper airways Air temperature in an enclosed fire can reach in excess of 600 8C. Due to a combination of efficient heat dissipation of the upper airway, reflex closure of the larynx and low heat capacity of air, direct thermal injury is usually confined to airway structures above the carina [16]. Thermal injuries to upper airway structures can, however, lead to massive swelling and partial or even total airway obstruction [16]. Airway swelling develops rapidly over a few hours, particularly as fluid resuscitation is ongoing, and may not peak until 24 hours post injury. Therefore evaluation immediately following the injury may be an unreliable indicator of the severity of obstruction that may develop, and it is essential that all patients suspected of having significant upper airway burns are carefully assessed by an experienced senior clinician for consideration of early elective intubation for airway protection. Endotracheal intubation has potential complications including the need for heavy sedation and even neuromuscular blockade; hypotension and ‘‘fluid creep’’; and tube misplacement, dislodgement, or blockage. ‘‘Prophylactic’’ intubation of all patients with inhalation injury should be avoided where safe to do so [17]. Chemical irritation of the respiratory tract Lower airway injury is usually caused by chemical irritation rather than thermal injury, and the nature and severity depends on the type of materials burnt, the temperature of combustion, and the duration of exposure or ‘dose’ [15]. Burnt rubber and plastics produce sulphur dioxide, nitrogen dioxide, ammonia and chlorine, which form corrosive acids and alkalis when combined with water in the alveoli. Hydrocarbons, aldehydes, ketones and acids form from polyethylene, while burning cotton or wool produce toxic aldehydes. Carbon monoxide and cyanide are generated from combustion of wood and polyurethane respectively. Studies using Multiple Inert Gas Elimination Technique (MIGET) suggest that the hypoxia associated with smoke-inhalation-induced small airways injury is predominantly due to V/Q mismatch [18].

The tragic Dellwood fire [19] shed some light on the histological process following smoke inhalation. Autopsy findings of infants who died revealed a combination of bronchial necrosis, alveolar congestion and atelectasis, with vascular engorgement and formation of dense membranes or casts obstructing the lower airways. Bronchiolitis and bronchopneumonia were observed in some. Pulmonary oedema due to increased vascular permeability plays an important role in the pathophysiological processes leading to lung injury. This is thought to be mediated in part by increased nitric oxide (NO) production, which forms a potent oxidant peroxynitrite (ONOO-), causing cellular injury and lipid peroxidation [20]. Chemicals in smoke promote the formation of neutrophil-generated oxygen radicals and inflammatory radicals which cause bronchial constriction, and exudate and airway cast formation. Impaired chemotactic and phagocytic function of the alveolar macrophage increases the risk of infection. Destruction and damage to the airway’s ciliary transport function leads to the accumulation of casts, airway plugging and impaired clearance of bacteria. The end result is progressive respiratory failure over the course of 48 hours due to decreased lung compliance, V/Q mismatch, and increased dead space ventilation. Systemic toxicity due to inhaled substances Carbon monoxide (CO) and cyanide inhalation can lead to major morbidity following inhalation injury. Carbon monoxide is an odourless, colourless gas with an affinity 200 times greater than oxygen for haemoglobin [11]. CO shifts the oxyhaemoglobin dissociation curve to the left, and, following prolonged exposure, binds to cytochrome oxidase, impairing mitochondrial function and reducing adenosine triphosphate production. Carbon monoxide thus reduces both the oxygen-carrying capacity of blood and oxygen dissociation at a tissue level, as well as disrupting cellular respiration. Standard pulse oximetry cannot reliably distinguish between oxyhaemoglobin and carboxyhaemoglobin (COHb), and patients may appear ‘cherry pink’ rather than cyanosed. Co-oximetry is required to make the diagnosis. Hydrogen cyanide is produced by combustion of various household materials. Cyanide inhibits the cytochrome oxidase system and may have a synergistic effect with carbon monoxide in producing tissue hypoxia, lactic acidosis and decreased cerebral oxygen consumption [21]. One study of smoke inhalation victims (with burns <15%) found a significant correlation between a lactate level of >10 mmol/L and an elevated blood cyanide level [22]. A lactic acidosis in burn victims may, however, be due to several causes and is not specific for cyanide toxicity. The in vitro half-life of cyanide is approximately 1 hour [22]. Although a number of potential ‘‘antidotes’’ for cyanide toxicity are available, a rapid diagnostic test for cyanide poisoning is not widely available, and as a result the accurate evaluation of the efficacy of these therapies remains difficult. DIAGNOSIS OF INHALATION INJURY The diagnosis of inhalation injury is suggested by a history of exposure to smoke, flames or super-heated air in an enclosed space, and duration of exposure (trapped or unconscious at the scene), together with physical findings of facial burns, upper airway injury (redness and swelling of the oropharynx, hoarseness, stridor, carbonaceous sputum) and lower airway involvement (tachypnoea, dyspnoea, crackles or wheeze, decreased breath sounds, decreased O2 saturations) [16,23]. The diagnosis can be confirmed and graded by fiberoptic bronchoscopy (Table 1) [9,24,25].

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Table 1 Bronchoscopic criteria used to grade inhalation injury {derived from reference [14]} Grade 0 - no injury: absence of carbonaceous deposits, erythema, edema, bronchorrhea, or obstruction Grade 1 - mild injury: minor or patchy areas of erythema, carbonaceous deposits in proximal or distal bronchi (any or combination) Grade 2 - moderate injury: moderate degree of erythema, carbonaceous deposits, bronchorrhea, with or without compromise of the bronchi (any or combination) Grade 3 - severe injury: severe inflammation with friability, copious carbonaceous deposits, bronchorrhea, bronchial obstruction (any or combination) Grade 4 (massive injury): evidence of mucosal sloughing, necrosis, endoluminal obliteration (any or combination)

Advances in the management of inhalational injury have been hampered by the lack of uniform criteria for diagnosis and severity grading [23]. Inhalation injury in children can largely be determined by clinical findings, with or without bronchoscopy [9]. A number of scoring systems have been developed in an effort to grade the severity of inhalation injury [26,27]; however, due to the heterogeneous presentation of burns patients, predicting which patients are vulnerable to increased pulmonary dysfunction, respiratory failure, and mortality has proved difficult [11]. Some authors, for instance, demonstrated a significant correlation between the severity of inhalation injury graded by bronchoscopy and fluid resuscitation volume [12,13], while others have not [14]. Liffner failed to demonstrate a relationship between their scoring system and the development of Acute Respiratory Distress Syndrome (ARDS) [27]. VENTILATORY STRATEGIES While intubation and ventilation must be considered early in cases of inhalational injury, it shouldn’t be performed without a careful consideration of the potential morbidity outlined above. Reasons for intubation include: protection against anticipated airway swelling; treatment of impaired oxygenation and/or ventilation due to lung injury; and to ensure airway protection and optimal oxygenation in cases of hypoxia or carbon monoxide poisoning with neurological impairment. In all cases, the goal of mechanical ventilation should be to optimise oxygenation and ventilation while minimising potential ventilator-induced lung injury (VILI). The mechanisms leading to VILI include: high airway pressure causing barotrauma; over-distension leading to volutrauma; repetitive opening and closing of alveoli causing atelectrauma; and lung inflammation secondary to the release of pro-inflammatory cytokines producing biotrauma. These have been extensively reviewed elsewhere [28,29]. As mentioned above, the pathophysiology of inhalation injury may involve airway oedema and secretions as well as fluid leak causing alveolar and interstitial oedema. If the former predominates, signs of airway obstruction with increased resistance will be present, whereas in the latter situation there will be decreased gas exchange and decreased lung compliance. Alveolar collapse is likely in both situations, and of course, most patients with inhalation injury will have a mixture of these pathologies, which will often change over time. Optimal conventional mechanical ventilation aims to ventilate the lung at the steepest point of its compliance curve by setting the level of peak end-expiratory pressure (PEEP) just above the lower inflection point of the inspiratory pressure-volume curve. A number of ventilator modalities have been used in the setting of inhalation injury, and Figure 1 is a simplified diagram depicting the different pressure waveforms generated by these.

Figure 1. Simplified pressure-time waveform depicting the various forms of ventilation used in inhalation injury (see text for explanation).

Conventional lung protective ventilation Amato [30] first described the benefit of a low tidal volume ventilator strategy in cases of Acute Lung Injury (ALI)/ARDS, findings subsequently replicated by the ARDSNet trial [31] and Villar [32]. Since then, the ‘‘open-lung’’ ventilation strategy using low-tidal volume ventilation and sufficient PEEP to maintain alveolar and airway patency has been widely advocated in cases of ALI/ARDS irrespective of underlying aetiology. Caution is required in extrapolating the ARDSNet strategy to paediatric patients generally [33] - and those with inhalational injury specifically - as none of the three studies above included paediatric patients, and the ARDSNet trial excluded patients with burns exceeding 30% body surface area. Whether a low tidal volume strategy of 6 ml/kg predicted body weight (PBW) is as beneficial in children as in adults remains unproven. A prospective observational study of paediatric ARDS in Australia and New Zealand found higher maximum and median tidal volumes were associated with reduced mortality, even after correction for severity of lung disease [34]. Another study found that ventilating children with ALI/ARDS with tidal volumes between 6-10 ml/kg was not associated with increased mortality [35]. A study from the Shriner’s Hospital for Children [36] found that children with inhalational injury ventilated with high tidal volumes had a decreased incidence of ARDS and reduced ventilator days. This study included 932 children treated from 1986 to 2014 with bronchoscopically-confirmed inhalational injury, 691 of whom were ventilated with either a high tidal volume (HTV, 15 +/ 3 ml/kg) or a low tidal volume (LTV, 9 +/ 3 ml/kg) strategy. In spite of significantly higher ventilator pressures and a higher incidence of pneumothoraces, patients in the HTV group had a significant reduction in ventilator days when compared to the LTV

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group. The mortality observed in the LTV group was almost a third lower (15%) than the HTV group (22%), however, this did not reach statistical significance. It should be noted that the groups compared were from two different eras over 29 years (HTV: 1986-1996, LTV: 1997-2014), and changes in patient demographics over this period raised questions regarding the generalisability of the findings. Inhalation injury involving secretions and debris in the airways as well as airway oedema and bronchoconstriction may have pronounced airway obstruction, and inasmuch as the pathology is similar to other obstructive airway conditions like severe asthma, pressure control ventilation (PCV) has at least theoretical advantages over volume controlled ventilation (VCV) [37]. Due to variable degrees of obstruction/airways resistance, different lung units will have a range of time constants. By applying a constant pressure throughout inspiration, PCV may lead to more even gas distribution, greater tidal volume for the same inspiratory pressure, and improved dynamic compliance. High Frequency Percussive Ventilation (HFPV) HFPV is a pneumatically driven, pressure-limited, time-cycled mode of ventilation that delivers high-frequency (450-600/min) sub-tidal bursts of gas superimposed on a biphasic inspiratory and expiratory pressure cycle [38,39]. During inspiration, lung volumes are progressively increased by repetitive diminishing sub-tidal volume deliveries until an oscillatory plateau is reached. The lung is then allowed to empty passively until the pre-set expiratory baseline is reached. The percussive airflow delivered by HFPV is believed to facilitate evacuation of debris resulting from epithelial sloughing, haemorrhage, and inflammation after inhalation injury. HFPV has been shown to produce better gas exchange at similar pressures when compared with conventional ventilation [40]. A study of 15 adults with inhalation injury found HFPV was associated with a significant improvement in oxygenation without increasing biomarkers of lung injury, suggesting that the mode was lung protective [41]. Initial reports from case series [42–45] demonstrated better gas exchange and lower incidence of pneumonia when HFPV was used on burns patients with inhalation injury. In a prospective randomized trial comparing HFPV to conventional ventilation in burned children with respiratory failure, Carman et al. [46] found patients ventilated using HFPV required significantly lower peak inspiratory pressure and achieved a significantly higher PaO2/FiO2 ratio compared to those on conventional ventilation, and concluded that HFPV is a safe and effective method of ventilation for paediatric burn patients. Reper’s study [47] revealed similar findings in adult patients. More recently, Chung [48] compared adult burn patients managed with HFPV or a low-tidal volume conventional ventilation strategy. HFPV resulted in similar clinical outcomes, however, significantly more patients on the low-tidal volume ventilation arm failed to meet ventilation and oxygenation goals and required rescue therapy with either HFPV or airway pressure release ventilation (APRV). These encouraging data on HFPV has led to some burns centres favouring the use of HFPV as their primary form of ventilation in inhalational injury. High Frequency Oscillatory Ventilation (HFOV) HFOV is a ventilation mode delivering rapid (5-15 Hz) sub-tidal oscillatory ‘breaths’ to improve gas exchange while providing lung protection. In contrast to HFPV, HFOV oscillates the lung around a constant mean airway pressure higher than that used in conventional ventilation. The application of a relatively high

constant mean airway pressure recruits collapsed alveoli and prevents alveolar derecruitment while avoiding high peak inspiratory pressures. The results of the OSCAR [49] and OSCILLATE [50] trials have cast doubt on HFOV use in ARDS. The OSCAR trial reported no mortality benefit with HFOV versus conventional ventilation while the OSCILLATE trial was stopped early due to an increase in mortality in the HFOV arm. Increased use of neuromuscular blockade and vasopressor support in the HFOV arm was noted in both trials. It should be noted that these studies included a heterogeneous group of patients with ARDS, and paediatric patients were excluded. Data for the use of HFOV in burns comes largely from single centre studies. Cartoto [51,52] reported improved oxygenation in adult burns patients with ARDS when HFOV was initiated. They concluded that HFOV should be considered where moderate to severe oxygenation failure (PaO2/FiO2 ratio <150) persists despite aggressive and escalating conventional mechanical ventilator support. Oxygenation failure in this context usually characterised by a need for either: an FiO2 >0.6 despite a PEEP of >12.5 cm H2O; the need for inverse ratio ventilation; the use of inhaled nitric oxide (iNO) to support oxygenation; or an oxygenation index ((FiO2 x mean airway pressure)/paO2 mmHg) >25. HFOV may be less effective in treating severe hypoxic respiratory failure associated with ARDS and concomitant inhalation injury than in ARDS and solely a burn injury [53]. The unique pathophysiologic changes in the lung parenchyma and airway following smoke inhalation, including small airway obstruction, may limit the ability of HFOV to recruit alveoli. In addition, there may be difficulty in managing secretions, potential worsening of gas trapping and related hypercapnia. Also HFOV complicates the intermittent nebulisation of adjunctive therapies for inhalation injury [54]. Experience from the Riley Hospital for Children [55] suggests this may be the case in children with burns. While most patients demonstrated an improvement in oxygenation following initiation of HFOV, they described a group of ‘‘slow responders’’, similar to Cartoto et al. There was a high incidence of barotrauma (38%) and a fifth of the patients had refractory hypercapnia on HFOV. Given the current evidence, HFOV should only be considered as rescue therapy for burn patients failing conventional mechanical ventilation, and when inhalational injury is present, it should be anticipated that the response to HFOV might be poor. Airway Pressure Release Ventilation APRV is a mode of ventilation where a constant high level of positive airway pressure is punctuated by brief intermittent releases of pressure [56]. The prolonged high pressure (Phigh) promotes alveolar recruitment and maintains lung volume, while the time-cycled release phase allows the lungs to periodically ‘decompress’ to a lower set pressure (Plow) which aids CO2 clearance. The patient is able to breathe spontaneously and independent of the ventilator cycle, allowing decreased use of sedation and neuromuscular blockade. Spontaneous breathing has a positive impact on cardiovascular function, renal function and splanchnic perfusion [57]. A number of excellent review articles on APRV have been published [57–59], however, there are few studies of APRV in patients with inhalation injury. Batchinsky et al. [60] compared APRV to conventional ventilation in pigs with inhalational injury and found that APRV-treated animals developed ARDS faster than conventional mechanical ventilation-treated animals, with a lower PaO2/FiO2 ratio at 12, 18, and 24 hours after injury. They postulated that the pathophysiologic changes of early smoke inhalation injury have important clinical implication that may limit the benefit of APRV. Further studies of APRV in the burns population are required.

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Non-Invasive Ventilation (NIV) NIV is defined as any form of ventilatory support applied without the use of an endotracheal tube, including continuous positive airway pressure (CPAP) [61]. The potential benefits of NIV are numerous, and stem from the avoidance of the morbidity associated with endotracheal intubation. Non-intubated patients can communicate freely, require less sedation, can cough and expectorate, are able to continue on standard oral intake, and avoid other potential complications of intubation such as oropharyngeal trauma, mucosal ulceration and ventilator associated pneumonia. Key to the success of NIV is an ability of the patient to protect his own airway, and NIV is contraindicated in unconscious patients with impaired cough and secretion clearance. Data regarding the use of NIV in burns patients is limited. Endorf et al. [62] recently proposed early application of NIV to a high-risk burn patient who does not require immediate intubation, even before signs of respiratory insufficiency appear, however, this strategy has not been tested in clinical trials. A retrospective study by Smailes [63] including 30 patients with burns found that for patients with respiratory insufficiency post-extubation, the use of NIV prevented reintubation in 74%. Only eight patients in this study had inhalation injury. Warner [64] reviewed 200 patients over a 6 year period at the Shriner’s Hospital for Children where 6 of 10 patients who received NIV postextubation for respiratory insufficiency avoided reintubation; none of the patients had inhalational injury, however. NIV mask application may be problematic in the setting of facial burns and the anxious, struggling child. Finally, there are legitimate concerns that NIV may mask signs of impending airway obstruction in the setting of an inhalational injury. Heated Humidified High-Flow Nasal Cannula (HHHFNC) HHHFNC delivers humidified gas via nasal cannula at flow rates exceeding minute ventilation. HHHFNC appears to reduce the work of breathing and improves gas exchange by nasopharyngeal dead-space washout; decreasing the energy required to humidify and heat respiratory gases; and by providing a degree of positive distending pressure [65]. HHHFNC has so far been found to be useful to support infants with bronchiolitis; premature neonates; and adults with hypoxic respiratory failure [66]. There are no reports of its use to date in patients with inhalation injury.

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[73] showed that a higher dose of heparin (10,000U vs 5,000U) nebulised with NAC led to a reduction in lung injury score and reduced ventilator days, suggesting a dose-dependent effect. The higher dose of heparin had no effect on systemic coagulation. However, a retrospective review by Holt [74] on 150 adult patients with inhalation injury showed no improvement in clinical outcome with the use of nebulised heparin/NAC. The use of nebulised adrenaline [75] and albuterol [76] in animals have shown promise in improving airway clearance, decreasing airway pressures and improving PaO2/FiO2 ratio. This is postulated to be due to beta-receptor induced bronchodilatory and anti-inflammatory effects. Other potentially useful therapies under investigation include thromboxane A2 antagonists, free oxygen radical scavengers and anti-muscarinic agents. CONCLUSION Inhalation injury remains a major cause of morbidity and mortality in children with burns worldwide. The optimal mode and settings for ventilating children with inhalation injury is currently unclear, and further studies are required. Until the results of such studies are known, patients with significant lung injury should be conventionally ventilated with a tidal volume of 5-8 mL/kg PBW, limitation of plateau pressure to 28cmH2O, and application of sufficient PEEP to maintain alveolar patency and adequate oxygenation [33]. Permissive hypercapnia should be accepted unless there is a concomitant neurological injury with suspected intracranial hypertension. HFPV has shown promise as an alternative mode of ventilation in some centres, and it may facilitate the clearance of airway debris and secretions. APRV and HFOV may be considered as ‘‘rescue modes’’ in very severe lung disease, though a benefit on outcome remains unproven. The efficacy and role of adjunctive pharmacologic therapies on outcomes in inhalation injury is unclear. Given the multitude of uncertainties in this important area, further research is needed to clarify the optimal management including ventilation strategy - for children with inhalation injury. It is important that such research look specifically at clinically important outcome measures such as 28-day mortality, and, given the heterogeneous patient population and relatively low mortality, these studies will likely need to be multicentre.

Pharmacological Adjuncts CONFLICTS OF INTEREST Adjuncts to ventilation seek to tackle the underlying pathophysiologic processes of inhalation injury. Although some are promising, there is little to no evidence of improved patient outcomes and wide variation in the use of many of these therapies. In an animal model of inhalation injury, those who received iNO had decreased lung water, decreased pulmonary microvascular resistance and decreased pulmonary artery pressure when compared with controls [67]. iNO has been used as rescue therapy in cases of refractory hypoxic respiratory failure following inhalation injury. Despite an improvement in PaO2/FiO2 ratio [68–70] no mortality benefit was demonstrated. In inhalation injury, casts formed by a combination of fibrin, mucus, inflammatory cells, and sloughed epithelial cells may lead to airway obstruction. Researchers have studied the use of nebulised anticoagulants to prevent fibrin formation in an effort to reduce airway cast formation. Desai [71] demonstrated that children with inhalation injury who received nebulised heparin and N-acetylcystine (NAC) had reduced reintubation rates as well as lower mortality. Miller et al. [72] found this treatment attenuated lung injury and the progression of ARDS in ventilated adult patients with ALI following smoke inhalation. El-Sharnouby

The authors declare that they have no conflicts of interest. FUTURE DIRECTIONS FOR RESEARCH 1. A widely agreed upon definition of inhalation injury is an essential first step to establishing multicentre research in this area. 2. Due to small patient numbers in individual centres and relatively low mortality, large, multi-centred randomised controlled trials comparing ventilator strategies (e.g. high vs. low tidal volume, HFPV vs. conventional ventilation) will be necessary to demonstrate clinically relevant outcome benefits (such as 28-day mortality). 3. The efficacy of pharmacologic adjuncts such as inhaled heparin and NAC should be subjected to rigorous controlled trials.

References [1] Smith DL, Cairns BA, Ramadan F, et al. Effect of inhalation injury, burn size, and age on mortality: a study of 1447 consecutive burn patients. J Trauma 1994;37:655–9.

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[2] Whitelock-Jones L, Bass DH, Millar AJ, et al. Inhalation burns in children. Pediatr Surg Int 1999;15:50–5. [3] Wolf SE, Rose JK, Desai MH, et al. Mortality determinants in massive pediatric burns. An analysis of 103 children with > or = 80% TBSA burns (> or = 70% fullthickness). Ann Surg 1997;225:554–65. discussion 565-559. [4] Spies M, Herndon DN, Rosenblatt JI, et al. Prediction of mortality from catastrophic burns in children. The Lancet 2003;361:989–94. [5] Colohan SM. Predicting prognosis in thermal burns with associated inhalational injury: a systematic review of prognostic factors in adult burn victims. J Burn Care Res 2010;31:529–39. [6] Shirani KZ, Pruitt Jr BA, Mason Jr AD. The influence of inhalation injury and pneumonia on burn mortality. Ann Surg 1987;205:82–7. [7] Veeravagu A, Yoon BC, Jiang B, et al. National trends in burn and inhalation injury in burn patients: results of analysis of the nationwide inpatient sample database. J Burn Care Res 2015;36:258–65. [8] Gore DC, Hawkins HK, Chinkes DL, et al. Assessment of adverse events in the demise of pediatric burn patients. J Trauma 2007;63:814–8. [9] Palmieri TL, Warner P, Mlcak RP, et al. Inhalation injury in children: a 10 year experience at Shriners Hospitals for Children. J Burn Care Res 2009;30:206–8. [10] Rosenberg M, Ramirez M, Epperson K, et al. Comparison of long-term quality of life of pediatric burn survivors with and without inhalation injury. Burns 2015;41:721–6. [11] Dries DJ, Endorf FW. Inhalation injury: epidemiology, pathology, treatment strategies. Scand J Trauma Resusc Emerg Med 2013;21:31. [12] Dai NT, Chen TM, Cheng TY, et al. The comparison of early fluid therapy in extensive flame burns between inhalation and noninhalation injuries. Burns 1998;24:671–5. [13] Navar PD, Saffle JR, Warden GD. Effect of inhalation injury on fluid resuscitation requirements after thermal injury. Am J Surg 1985;150:716–20. [14] Endorf FW, Gamelli RL. Inhalation injury, pulmonary perturbations, and fluid resuscitation. J Burn Care Res 2007;28:80–3. [15] Lee AS, Mellins RB. Lung injury from smoke inhalation. Paediatr Respir Rev 2006;7:123–8. [16] McCall JE, Cahill TJ. Respiratory care of the burn patient. J Burn Care Rehabil 2005;26:200–6. [17] Oscier C, Emerson B, Handy JM. New perspectives on airway management in acutely burned patients. Anaesthesia 2014;69:105–10. [18] Shimazu T, Yukioka T, Ikeuchi H, et al. Ventilation-perfusion alterations after smoke inhalation injury in an ovine model. J Appl Physiol (1985) 1996; 81: 2250–2259. [19] Cox ME, Heslop BF, Kempton JJ, et al. The Dellwood fire. Br Med J 1955;1:942–6. [20] Soejima K, Traber LD, Schmalstieg FC, et al. Role of nitric oxide in vascular permeability after combined burns and smoke inhalation injury. Am J Respir Crit Care Med 2001;163:745–52. [21] Moore SJ, Ho IK, Hume AS. Severe hypoxia produced by concomitant intoxication with sublethal doses of carbon monoxide and cyanide. Toxicol Appl Pharmacol 1991;109:412–20. [22] Baud FJ, Barriot P, Toffis V, et al. Elevated blood cyanide concentrations in victims of smoke inhalation. N Engl J Med 1991;325:1761–6. [23] Woodson LC. Diagnosis and grading of inhalation injury. J Burn Care Res 2009;30:143–5. [24] Edelman DA, White MT, Tyburski JG, et al. Factors affecting prognosis of inhalation injury. J Burn Care Res 2006;27:848–53. [25] Marek K, Piotr W, Stanislaw S, et al. Fibreoptic bronchoscopy in routine clinical practice in confirming the diagnosis and treatment of inhalation burns. Burns 2007;33:554–60. [26] Brown DL, Archer SB, Greenhalgh DG, et al. Inhalation injury severity scoring system: a quantitative method. J Burn Care Rehabil 1996;17:552–7. [27] Liffner G, Bak Z, Reske A, et al. Inhalation injury assessed by score does not contribute to the development of acute respiratory distress syndrome in burn victims. Burns 2005;31:263–8. [28] Slutsky AS, Ranieri VM. Ventilator-induced lung injury. N Engl J Med 2013;369:2126–36. [29] Gattinoni L, Protti A, Caironi P, et al. Ventilator-induced lung injury: the anatomical and physiological framework. Crit Care Med 2010;38:S539–48. [30] Amato MB, Barbas CS, Medeiros DM, et al. Effect of a protective-ventilation strategy on mortality in the acute respiratory distress syndrome. N Engl J Med 1998;338:347–54. [31] Ventilation with lower tidal volumes as compared with traditional tidal volumes for acute lung injury and the acute respiratory distress syndrome. The Acute Respiratory Distress Syndrome Network. N Engl J Med 2000; 342:1301–1308. [32] Villar J, Kacmarek RM, Perez-Mendez L, et al. A high positive end-expiratory pressure, low tidal volume ventilatory strategy improves outcome in persistent acute respiratory distress syndrome: a randomized, controlled trial. Crit Care Med 2006;34:1311–8. [33] Rimensberger PC, Cheifetz IM, Pediatric Acute Lung Injury Consensus Conference G. Ventilatory support in children with pediatric acute respiratory distress syndrome: proceedings from the Pediatric Acute Lung Injury Consensus Conference. Pediatr Crit Care Med 2015;16:S51–60. [34] Erickson S, Schibler A, Numa A, et al. Acute lung injury in pediatric intensive care in Australia and New Zealand-A prospective, multicenter, observational study*. Pediatr Crit Care Med 2007;8:317–23. [35] Khemani RG, Conti D, Alonzo TA, et al. Effect of tidal volume in children with acute hypoxemic respiratory failure. Intensive Care Med 2009;35:1428–37.

[36] Sousse LE, Herndon DN, Andersen CR, et al. High tidal volume decreases adult respiratory distress syndrome, atelectasis, and ventilator days compared with low tidal volume in pediatric burned patients with inhalation injury. J Am Coll Surg 2015;220:570–8. [37] Sarnaik AP, Daphtary KM, Meert KL, et al. Pressure-controlled ventilation in children with severe status asthmaticus. Pediatr Crit Care Med 2004;5:133–8. [38] Allan PF, Osborn EC, Chung KK, et al. High-frequency percussive ventilation revisited. J Burn Care Res 2010;31:510–20. [39] Salim A, Martin M. High-frequency percussive ventilation. Crit Care Med 2005;33:S241–5. [40] Lucangelo U, Zin WA, Fontanesi L, et al. Early short-term application of highfrequency percussive ventilation improves gas exchange in hypoxemic patients. Respiration 2012;84:369–76. [41] Reper P, Heijmans W. High-frequency percussive ventilation and initial biomarker levels of lung injury in patients with minor burns after smoke inhalation injury. Burns 2015;41:65–70. [42] Cioffi WG, Graves TA, McManus WF, et al. High-frequency percussive ventilation in patients with inhalation injury. J Trauma 1989;29:350–4. [43] Cioffi Jr WG, Rue 3rd LW, Graves TA, et al. Prophylactic use of high-frequency percussive ventilation in patients with inhalation injury. Ann Surg 1991;213:575–80. discussion 580–572. [44] Cortiella J, Mlcak R, Herndon D. High frequency percussive ventilation in pediatric patients with inhalation injury. J Burn Care Rehabil 1999;20: 232–5. [45] Reper P, Dankaert R, van Hille F, et al. The usefulness of combined highfrequency percussive ventilation during acute respiratory failure after smoke inhalation. Burns 1998;24:34–8. [46] Carman B, Cahill T, Warden G, et al. A prospective, randomized comparison of the Volume Diffusive Respirator vs conventional ventilation for ventilation of burned children. 2001 ABA paper. J Burn Care Rehabil 2002;23:444–8. [47] Reper P, Wibaux O, Van Laeke P, et al. High frequency percussive ventilation and conventional ventilation after smoke inhalation: a randomised study. Burns 2002;28:503–8. [48] Chung KK, Wolf SE, Renz EM, et al. High-frequency percussive ventilation and low tidal volume ventilation in burns: a randomized controlled trial. Crit Care Med 2010;38:1970–7. [49] Young D, Lamb SE, Shah S, et al. High-frequency oscillation for acute respiratory distress syndrome. N Engl J Med 2013;368:806–13. [50] Ferguson ND, Cook DJ, Guyatt GH, et al. High-frequency oscillation in early acute respiratory distress syndrome. N Engl J Med 2013;368:795–805. [51] Cartotto R, Cooper AB, Esmond JR, et al. Early clinical experience with highfrequency oscillatory ventilation for ARDS in adult burn patients. J Burn Care Rehabil 2001;22:325–33. [52] Cartotto R, Ellis S, Smith T. Use of high-frequency oscillatory ventilation in burn patients. Crit Care Med 2005;33:S175–81. [53] Cartotto R, Walia G, Ellis S, et al. Oscillation after inhalation: high frequency oscillatory ventilation in burn patients with the acute respiratory distress syndrome and co-existing smoke inhalation injury. J Burn Care Res 2009;30:119–27. [54] Cartotto R. Use of high frequency oscillatory ventilation in inhalation injury. J Burn Care Res 2009;30:178–81. [55] Greathouse ST, Hadad I, Zieger M, et al. High-frequency oscillatory ventilators in burn patients: experience of Riley Hospital for Children. J Burn Care Res 2012;33:425–35. [56] Downs JB, Stock MC. Airway pressure release ventilation: a new concept in ventilatory support. Crit Care Med 1987;15:459–61. [57] Porhomayon J, El-Solh AA, Nader ND. Applications of airway pressure release ventilation. Lung 2010;188:87–96. [58] Dries DJ, Marini JJ. Airway pressure release ventilation. J Burn Care Res 2009;30:929–36. [59] Seymour CW, Frazer M, Reilly PM, et al. Airway pressure release and biphasic intermittent positive airway pressure ventilation: are they ready for prime time? J Trauma 2007;62:1298–308. discussion 1308–1299. [60] Batchinsky AI, Burkett SE, Zanders TB, et al. Comparison of airway pressure release ventilation to conventional mechanical ventilation in the early management of smoke inhalation injury in swine. Crit Care Med 2011;39: 2314–21. [61] Evans TW. International Consensus Conferences in Intensive Care Medicine: Non-invasive positive pressure ventilation in acute respiratory failure. Intensive Care Med 2000;27:166–78. [62] Endorf FW, Dries DJ. Noninvasive ventilation in the burned patient. J Burn Care Res 2010;31:217–28. [63] Smailes ST. Noninvasive Positive Pressure Ventilation in burns. Burns 2002;28:795–801. [64] Warner P. Noninvasive positive pressure ventilation as an adjunct to extubation in the burn patient. J Burn Care Res 2009;30:198–9. [65] Hutchings FA, Hilliard TN, Davis PJ. Heated humidified high-flow nasal cannula therapy in children. Arch Dis Child 2015;100:571–5. [66] Frat JP, Thille AW, Mercat A, et al. High-flow oxygen through nasal cannula in acute hypoxemic respiratory failure. N Engl J Med 2015;372:2185–96. [67] Enkhbaatar P, Kikuchi Y, Traber LD, et al. Effect of inhaled nitric oxide on pulmonary vascular hyperpermeability in sheep following smoke inhalation. Burns 2005;31:1013–9. [68] Musgrave MA, Fingland R, Gomez M, et al. The use of inhaled nitric oxide as adjuvant therapy in patients with burn injuries and respiratory failure. J Burn Care Rehabil 2000;21:551–7.

C.T. Goh, S. Jacobe / Paediatric Respiratory Reviews 20 (2016) 3–9 [69] Sheridan RL, Hurford WE, Kacmarek RM, et al. Inhaled nitric oxide in burn patients with respiratory failure. J Trauma 1997;42:629–34. [70] Sheridan RL, Zapol WM, Ritz RH, et al. Low-dose inhaled nitric oxide in acutely burned children with profound respiratory failure. Surgery 1999;126:856–62. [71] Desai MH, Mlcak R, Richardson J, et al. Reduction in mortality in pediatric patients with inhalation injury with aerosolized heparin/N-acetylcystine therapy. J Burn Care Rehabil 1998;19:210–2. [72] Miller AC, Rivero A, Ziad S, et al. Influence of nebulized unfractionated heparin and N-acetylcysteine in acute lung injury after smoke inhalation injury. J Burn Care Res 2009;30:249–56.

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[73] Elsharnouby NM, Eid HE, Abou Elezz NF, et al. Heparin/N-acetylcysteine: an adjuvant in the management of burn inhalation injury: a study of different doses. J Crit Care 2014;29:182. e181-184. [74] Holt J, Saffle JR, Morris SE, et al. Use of inhaled heparin/N-acetylcystine in inhalation injury: does it help? J Burn Care Res 2008;29:192–5. [75] Lange M, Hamahata A, Traber DL, et al. Preclinical evaluation of epinephrine nebulization to reduce airway hyperemia and improve oxygenation after smoke inhalation injury. Crit Care Med 2011;39:718–24. [76] Palmieri TL, Enkhbaatar P, Bayliss R, et al. Continuous nebulized albuterol attenuates acute lung injury in an ovine model of combined burn and smoke inhalation. Crit Care Med 2006;34:1719–24.