Open Access

Diagnosis and management of inhalation injury: an updated review

  • Patrick F. Walker1,
  • Michelle F. Buehner2Email author,
  • Leslie A. Wood3,
  • Nathan L. Boyer3,
  • Ian R. Driscoll4,
  • Jonathan B. Lundy4,
  • Leopoldo C. Cancio4 and
  • Kevin K. Chung4, 5
Critical Care201519:351

https://doi.org/10.1186/s13054-015-1077-4

Published: 28 October 2015

Abstract

In this article we review recent advances made in the pathophysiology, diagnosis, and treatment of inhalation injury. Historically, the diagnosis of inhalation injury has relied on nonspecific clinical exam findings and bronchoscopic evidence. The development of a grading system and the use of modalities such as chest computed tomography may allow for a more nuanced evaluation of inhalation injury and enhanced ability to prognosticate. Supportive respiratory care remains essential in managing inhalation injury. Adjuncts still lacking definitive evidence of efficacy include bronchodilators, mucolytic agents, inhaled anticoagulants, nonconventional ventilator modes, prone positioning, and extracorporeal membrane oxygenation. Recent research focusing on molecular mechanisms involved in inhalation injury has increased the number of potential therapies.

Introduction

Despite important advances in the care of patients with inhalation injury, which continues to be largely supportive, morbidity and mortality remain high [1]. Inhalation injury can feature supraglottic thermal injury, chemical irritation of the respiratory tract, systemic toxicity due to agents such as carbon monoxide (CO) and cyanide, or a combination of these insults. The resultant inflammatory response may cause higher fluid resuscitation volumes, progressive pulmonary dysfunction, prolonged ventilator days, increased risk of pneumonia, and acute respiratory distress syndrome (ARDS) [2, 3].

In this review we describe the recent advances made in our understanding of the pathophysiology of inhalation injury, diagnostic criteria and injury severity, complications, current treatment options, and future avenues of research.

Pathophysiology

Inhalation injury complicates burns in approximately 10 to 20 % of patients and significantly increases morbidity and mortality [25]. Other factors associated with a significant effect on mortality include burn size and age [6, 7] and the incidence of inhalation injury is correlated with an increase in both these factors [6, 7]. Inhalation injury has also been found to be an independent predictor of mortality in burn patients [8] and worsens survival even among patients with similar age and burn size [8]. Thermal airway injury is generally limited to supraglottic structures, whereas injury to the lower airway is chemical in nature. In the setting of steam, however, the injury is pervasive, causing damage to both upper airways and direct thermal injury to the lungs [9]. The degree of inhalation injury is variable and is dependent on several factors: the gas components inhaled, the presence of particulate matter (soot), the magnitude of the exposure, and individual host factors such as underlying lung disease and inability to flee the incident.

Historically, it was speculated that the combustion of certain materials, such as noncommercial polyurethane foam, resulted in the formation of a neurotoxin [10]; however, newer material testing methods revealed most smoke toxicity can be explained by a small number of toxic gases exerting their effects through asphyxiation, systemic toxicity, or direct effects on respiratory tissue [11]. Many products of combustion, such as carbon dioxide, function as simple asphyxiants by displacing oxygen at the alveolar level. This is further exacerbated by the hypoxic fire environment. CO functions systemically as an asphyxiant by (1) competitively displacing oxygen from hemoglobin and (2) binding to cytochrome oxidase at the mitochondrial level. By contrast, hydrogen cyanide binds only to cytochrome oxidase [1].

Other combustion products, such as halogen acids, formaldehyde, and unsaturated aldehydes (for example, acrolein), function as respiratory irritants. The chemical irritation causes denuding of the respiratory mucosa, leading to sloughing within the airways, and induces the host inflammatory response. Furthermore, the chemical injury stimulates vasomotor and sensory nerve endings to produce neuropeptides. Preclinical studies have shown these neuropeptides can induce an inflammatory response [12]. Substance P and calcitonin gene-related peptide are two suggested neuropeptides inducing tissue injury after inhalation injury [12, 13]. Lange et al. [13] found antagonists to calcitonin gene-related peptide and substance P attenuated the fluid shifts/inflammation in an ovine model subjected to smoke and inhalation injury. These neuropeptides then induce bronchoconstriction and nitric oxide synthase (NOS) to generate reactive oxygen species (ROS) [14]. As described by Kraneveld and Nijkamp [14], these neuropeptides can function as tachykinins, inducing a robust inflammatory response with the downstream effects of bronchoconstriction, increased vascular permeability, and vasodilation. Furthermore, tachykinins like substance P and neurokinin A can modulate immune cells and stimulate neutrophil and eosinophil chemotaxis [14].

Overall, these factors potentiate local cellular damage and the loss of hypoxic pulmonary vasoconstriction. The loss of hypoxic pulmonary vasoconstriction causes bronchial blood flow to increase by a factor of 10 within 20 min of inhalation injury. ROS may also induce mitochondrial dysfunction and cellular apoptosis [15]. Tissue factor expressed by damaged respiratory epithelial cells and alveolar macrophages initiates the extrinsic coagulation cascade, disrupting pro- and anti-coagulant alveolar homeostasis. We found, for example, that smoke inhalation injury contributes to a hypercoagulable state in the lung by inducing plasminogen activator inhibitor 1 and stabilizing its mRNA [16].

In addition, the increased bronchial blood flow delivers activated polymorphonuclear leukocytes and cytokines to the lung, potentiating the host inflammatory response. The loss of an intact bronchial epithelium and the effects of ROS result in a loss of plasma proteins and fluid from the intravascular space into the alveoli and bronchioles [17]. The transvascular shift of protein causes exudate and cast formation within the airways, leading to alveolar collapse or complete occlusion of the airways [17]. Experimental measures to decrease bronchial blood flow show attenuation of airway obstruction, pulmonary edema, and improved oxygenation [18]. These processes - loss of hypoxic vasoconstriction, increased blood flow to injured lung segments, decreased ventilation of collapsed segments - contribute to ventilation-perfusion mismatch as a primary mechanism of hypoxemia following the smoke inhalation injury [19]. Atelectasis, dysfunction of the immune system, and mechanical ventilation, in turn, predispose to pneumonia as a common complication of inhalation injury.

Many studies are now being completed to better understand the role pro- and anti-inflammatory mediators, or other immune modulators, play in patient outcomes. Albright et al. [1] demonstrated a graded increase in inflammatory cytokines from bronchoalveolar lavage fluid (IL-4, IL-6, IL-9, IL-15, interferon-gamma, granulocyte macrophage colony-stimulating factor, monocyte chemoattractant protein-1) that correlates with the severity of inhalation injury noted on bronchoscopic evaluation (grades 3 or 4 versus 1 or 2). They also found a significant shift from a macrophage-predominant population of cells in lavage fluid to one dominated by neutrophils [1]. This is thought to contribute to the later immune dysfunction, bacterial overgrowth, and pneumonia [1]. The source of the cytokines identified in inhalation is thought to be secondary to complement activation by heat denatured proteins [20]. The stimulation of the complement cascade releases histamine, resulting in xanthine oxidase upregulation and ROS formation [20, 21].

Davis et al. [22] showed several plasma immune mediators were associated with increased inhalation injury severity, even after adjusting for age and percentage of total body surface area burned. IL-1 receptor antagonist (IL-1RA), an anti-inflammatory immune mediator, had the strongest correlation with injury severity and outcome measures, including mortality [22]. The authors also found a much lower IL-1β to IL-1RA ratio in patients with inhalation injury who died. Given that IL-1β is an essential component of the host defense, they hypothesized that insufficient IL-1β or excessive IL-1RA results in systemic immune dysfunction.

The formation of ROS, such as superoxide anions (O2 ), hydrogen peroxide (H2O2), and hydroxyl radicals (OH; the most unstable and reactive), appears to play a major role in numerous injury models [23]. Under normal circumstances the body has compensatory antioxidant mechanisms to mitigate the effects of ROS. Following reperfusion or injury, however, there is a large burst of ROS, which overwhelm the body’s protective measures. As a result, the ROS can lead to cell injury through neutrophil attraction and cytokine production. Indeed, evidence of oxidative stress is found in plasma and lung tissue following smoke inhalation injury [24]. IL-8, a potent chemokine, has been suggested to play a vital role in the initiation and progression of lung inflammation after smoke inhalation [25]. NOS-dependent formation of ROS has been studied in inhalation injury. Activated neutrophils produce large quantities of superoxide that combine with nitric oxide to produce peroxynitrite, which can damage DNA [20]. Peroxynitrite and the resultant DNA damage stimulates poly-(ADP ribose) polymerase-1 (PARP-1), a nuclear repair enzyme and coactivator of NF-ĸB, which can deplete ATP and produce cell damage [26, 27]. Combined, these factors contribute to an increase in IL-8 [27], induce NOS, neutrophil chemotaxis, and increase ROS production [20]. For this reason, heparin/acetylcysteine combinations are being utilized as ROS scavengers in inhalation injury [20].

Diagnosis

Classically, the diagnosis of inhalation injury was subjective and made on the basis of clinical findings. When evaluating a patient with suspected inhalation injury, a clinician first reviews the history and reported mechanism to determine the likelihood of an inhalation injury. Pertinent information includes exposure to flame, smoke, or chemicals (industrial and household), duration of exposure, exposure in an enclosed space, and loss of consciousness or disability. Pertinent physical exam findings include facial burns, singed facial or nasal hair, soot or carbonaceous material on the face or in the sputum, and signs of airway obstruction including stridor, edema, or mucosal damage [3]. Older patients, and those with more extensive burns, are at increased risk of inhalation injury because of prolonged exposure to the fire environment [8].

There are several modalities for confirming inhalation injury to include fiberoptic bronchoscopy (FOB), chest computed tomography (CT), carboxyhemoglobin measurement, radionuclide imaging with 133Xenon, and pulmonary function testing. Many of these modalities lack sensitivity, are invasive, or are subject to significant variability between institutions. In studies by Shirani et al. [8], the following gradation of morbidity and mortality risk was seen in order of increasing risk: (1) patients without inhalation injury; (2) patients with inhalation injury by 133Xenon scan only, but not by FOB; and (3) patients with inhalation injury by FOB. Also, presence of inhalation injury on FOB predicted risk of acute lung injury and the need for increased fluid resuscitation volumes. More recent studies have found a significant correlation between the severity of inhalation injury on FOB and mortality [28].

There are several difficulties in diagnosing the presence and severity of inhalation injuries. Although several laboratories have developed dose–response models of inhalation injury in large animals [29], the characteristics of the material inhaled are important in determining the degree of respiratory failure. In addition, differences in the individual host inflammatory response may lead to a heterogeneous clinical presentation [30]. FOB is unable to assess distal airways and respiratory bronchioles; therefore, damage to this portion of the lung has been proposed as an explanation for the discordance between bronchoscopic severity of injury and mortality. Despite these limitations, FOB continues to be the standard technique used to assess the presence and severity of inhalation injury. Its relative ease and availability allows the initial diagnosis to be made (Fig. 1), and allows the inhalation injury to be followed serially (Figs. 2 and 3).
Fig. 1

Fiberoptic bronchoscopy of patient on post-burn day 0

Fig. 2

Fiberoptic bronchoscopy of patient on post-burn day 4

Fig. 3

Fiberoptic bronchoscopy of patient on post-burn day 10

Given the lack of a widely standardized and validated method for scoring inhalation injury severity, Woodson [30] has proposed a large multicenter study to create such a scoring system to allow for more reliable prognostic estimations. To date, no such study has been done, though one is currently underway based on clinical, radiographic, bronchoscopic, and biochemical parameters (ClinicalTrials.gov identifier NCT01194024).

Multiple studies have demonstrated that inhalation injury is a graded phenomenon with severity correlating with outcome. The Abbreviated Injury Score grading scale for inhalation injury on bronchoscopy has been shown to correlate with an increase in mortality as well impaired gas exchange [1, 28, 31]. This scale is shown in Table 1. Endorf and Gamelli [3] found that patients with more severe inhalation injury on initial bronchoscopy (grades 2, 3, 4) had worse survival rates than patients with lower scores (grades 0 or 1) (P = 0.03). They also noted the highest-grade inhalation injuries were not necessarily associated with an increased fluid requirement, contrary to prior data. Lastly, they found patients with an arterial partial pressure of oxygen (PaO2)/fraction of inspired oxygen (FiO2) ratio <350 upon presentation had a statistically significant increase in fluid resuscitation needs compared with patients with a ratio >350 (P = 0.03) [3]. Ryan et al. [32] have stated that, at this time, the most reliable indicator of the impact of inhalation injury is the PaO2/FiO2 ratio after the resuscitation has started. This is based on a retrospective review by Hassan et al. [28] of 105 patients admitted with inhalation injury. They assessed respiratory function by using the PaO2/FiO2 ratio from 0 to 192 h after injury. Their study showed a significant difference (P < 0.01) in PaO2/FiO2 ratios between patients who died (mean PaO2/FiO2 ratio 20.17) and those who survived (mean PaO2/FiO2 ratio 32.24). Ultimately, they propose to use PaO2/FiO2 ratio as a predictor of survival once the initial burn resuscitation has been completed and a full response to injury is able to be mounted [28]. Similarly, Cancio et al. [33] found that the mean alveolar-arterial oxygen gradient during the first 2 days was an independent predictor of mortality in mechanically ventilated burn patients. It is important to note that PaO2/FiO2 can be arbitrarily high or low depending on the choice of ventilator mode. In addition, PaO2/FiO2 may be affected by the volume of resuscitation. Therefore, we do not use PaO2/FiO2 as a basis for diagnosis of inhalation injury, but use it to trend the patient’s oxygenation and potential need for nonconventional ventilation.
Table 1

Abbreviated Injury Score grading scale for inhalation injury on bronchoscopy [1]

Grade

Class

Description

0

No injury

Absence of carbonaceous deposits, erythema, edema, bronchorrhea, or obstruction

1

Mild injury

Minor or patchy areas of erythema, carbonaceous deposits, bronchorrhea, or bronchial obstruction

2

Moderate injury

Moderate degree of erythema, carbonaceous deposits, bronchorrhea, or bronchial obstruction

3

Severe injury

Severe inflammation with friability, copious carbonaceous deposits, bronchorrhea, or obstruction

4

Massive injury

Evidence of mucosal sloughing, necrosis, endoluminal obstruction

Other means of evaluating the severity of inhalation injury include chest CT. First, a scoring system for severity of CT scan findings has been developed [29]. Our group studied 25 patients with inhalation injury and 19 patients without inhalation injury who received a chest CT within 24 h of admission [34]. The severity of radiographic findings was calculated by looking at 1-cm axial slices from the chest CT and these were scored by adding the highest radiologist’s score (RADS) for each quadrant. The RADS scoring system is shown in Table 2, and the various RADS findings are shown in Fig. 4. Our group assessed a composite endpoint of pneumonia, acute lung injury/ARDS, and death. We found that the detection of inhalation injury on bronchoscopy was associated with an 8.3-fold increase in the composite endpoint. A high RADS score (>8 per slice) in addition to a positive bronchoscopy was associated with a 12.7-fold increase, thus showing the potential for chest CT to complement bronchoscopy in detecting clinically significant inhalation injury [34].
Table 2

Radiologist’s scoring table (RADS score) for inhalation injury [34]

Finding

Score

Normal

0

Increased interstitial markings

1

Ground glass opacification

2

Consolidation

3

Fig. 4

Example of radiologist’s score findings in chest computed tomography scan slice [34]

Second, Yamamura et al. [35] used CT imaging to measure bronchial wall thickness 2 cm distal to the tracheal bifurcation in patients who had sustained an inhalation injury. The authors noted a statistically significant correlation between bronchial wall thickness and the development of pneumonia, total number of ventilator days, and ICU length of stay. They also found that a bronchial wall thickness value of >3.0 mm predicted the development of pneumonia with a sensitivity of 79 % and specificity of 96 %. Interestingly, this study was not able to replicate the association between Abbreviated Injury Score bronchoscopic scoring and clinical outcomes as described above [35].

A third approach to using the CT scan is virtual bronchoscopy. A three-dimensional reconstructed image is presented in such a way that the viewer navigates through the lung as if using a bronchoscope. We found that virtual bronchoscopy agrees best with FOB in the detection of airway narrowing, and less so in the detection of blistering or necrosis [36].

Problems with using chest CT as part of a diagnostic algorithm for inhalation injury include determining the optimal timing of the test and how to interpret abnormal radiographic findings in the setting of a negative bronchoscopy. Putman et al. [37] found that chest radiography on admission was rarely helpful in determining the presence or severity of inhalation injury, but its use is helpful as a baseline for determining future changes.

Respiratory support

Given the limited availability of targeted therapies for inhalation injury, one of the fundamental tenets is supportive respiratory care. This includes aggressive pulmonary toilet and mechanical ventilation when indicated. It should be noted that approximately 20 to 33 % of patients hospitalized with inhalation injury experience some degree of upper airway obstruction due to pharyngeal edema that can progress rapidly [38]. As thermal injury increases airway edema and can lead to airway obstruction, early intubation is favored [4]. This is of particular concern in patients who receive large amounts of intravenous fluids during resuscitation. Generally speaking, the most experienced clinician in airway management should perform endotracheal intubation with the largest available, age-appropriate endotracheal tube for patients with suspected or impending upper airway obstruction in the setting of inhalation injury. One study suggests prophylactic intubation can decrease mortality related to pulmonary-related death in patients with inhalation injury [39].

Maintaining bronchial hygiene is paramount in patients who have suffered inhalation injury. Early ambulation, chest physiotherapy, airway suctioning, and therapeutic bronchoscopy are adjunctive tools [38]. Reper et al. [40] demonstrated that intrapulmonary percussive ventilation administered through a face mask to spontaneously breathing patients with smoke inhalation injury, hypoxia, and persistent atelectasis can result in a significant improvement in PaO2/FiO2 ratio.

A low threshold should be maintained for intubation and mechanical ventilation in inhalation injury due to the progressive nature of the airway edema. Interestingly, a study by Mackie et al. [41] showed an increased use of mechanical ventilation in patients at a Dutch burn center from 1997 to 2006 (76 %) compared with 1987 to 1996 (38 %) despite a decrease in the incidence of inhalation injury (34 % versus 27 %). The authors hypothesized that this was related to the institution of Advanced Trauma Life Support principles in the mid-1990s in the Netherlands. Mackie [42] also suggested mechanical ventilation may be a significant contributor to mortality in burn patients independent of inhalation injury. He proposed increased intrathoracic pressure from positive pressure ventilation led to decreased venous return, followed by decreased cardiac and urine output. The typical clinical reaction is to increase intravenous fluid administration, resulting in higher volumes of infused fluid, a known risk factor for adverse outcomes in burn patients [42].

Multiple challenges, to include concern for ventilator-induced lung injury in patients with inhalation injury, have led to the use of unconventional ventilator modes [43].

Conventional mechanical ventilation is limited in the patient with inhalation injury. In a patient with fibrin casts, extensive chest wall thermal injuries, or high volumes of resuscitative fluid maintaining the recommended tidal volumes of less than 7 ml/kg body weight and plateau pressures of less than 30 cm water [44], can prove difficult with conventional techniques. Therefore, in order to apply lung-protective ventilation in patients with inhalation injury, nonconventional ventilator modes are employed.

High-frequency percussive ventilation (HFPV) was first described in patients with inhalation injury as a means of assisting with clearance of sloughed respiratory mucosa and plugs, as well as decreasing iatrogenic barotrauma and the incidence of pulmonary infection [45]. Further studies have demonstrated benefits from using HFPV prophylactically (that is, not as a salvage mode) in both adult [46, 47] and pediatric populations [48]. Our group performed a randomized controlled trial to compare HFPV versus conventional low tidal volume (LTV) ventilation [49]. While we detected no difference in ventilator-free days between patients randomized to HFPV compared with LTV ventilation, there was a statistically significant increase in the PaO2/FiO2 ratio for the HFPV cohort on days 0 to 3 (Fig. 5). We also found that less patients in the HFPV cohort required conversion to a rescue mode of ventilation compared with the LTV ventilation cohort [49]. Also, HFPV was associated with a decrease in the incidence of pneumonia from 45 to 26 % (P < 0.005) and resulted in an improvement in survival [46]. Although HFPV cannot reverse the effects of inhalation injury, it can improve the clearance of secretions, provide positive pressure throughout the ventilator cycle, allow for lower airway pressures, and increase functional reserve capacity [46].
Fig. 5

Comparison of the PaO2/FiO2 ratio over time between high frequency percussive ventilation (HFPV) and low-tidal volume ventilation (LTV) (asterisks denote P < 0.05) [49]

Interestingly, a recent retrospective study by Sousse et al. [50] compared high tidal volume (HTV) ventilation (15 ± 3 ml/kg, n = 190) with LTV ventilation (9 ± 3 ml/kg, n = 501) in pediatric patients suffering from inhalation injury. Patients on HTV had fewer days on the ventilator (P < 0.005), increased maximum peak inspiratory pressure (P < 0.02), and plateau pressures (P < 0.02) compared with those on LTV ventilation. Furthermore, the incidence of atelectasis and ARDs was significantly lower in the cohort receiving HTV ventilation (P < 0.0001 and P < 0.02, respectively). However, the HTV ventilation group were not without complications and had a significantly higher rate of pneumothorax compared with the LTV ventilation group (P < 0.03). For pediatric patients suffering from inhalation injury, HTV ventilation may be better than traditional LTV ventilation [50]. The mechanisms for this observation are unclear, but this study, much like the previous study, suggests that we must be cautious when extrapolating LTV ventilation to all patient populations, especially in those with different pathophysiologies. A randomized controlled trial may be necessary to tease out the true impact of these divergent strategies. Our group also looked at airway pressure release ventilation (APRV) in a prospective animal model study. We found that PaO2/FiO2 ratios were initially lower in pigs with inhalation injury on APRV compared with conventional mechanical ventilation, although this equilibrated at 48 h. Higher mean airway pressures were necessary to maintain oxygenation in APRV, and, in the end, no survival difference was seen between APRV and conventional mechanical ventilation [51].

Other nonventilator adjuncts to consider for inhalation injury include prone positioning and extracorporeal membrane oxygenation (ECMO). Our group showed that prone positioning led to a statistically significant increase in PaO2/FiO2 ratio in patients with inhalation injury and refractory ARDS whose initial ratio was an average of 87 ± 38 [52].

A systematic review and meta-analysis on the use of ECMO in inhalation injury was limited by number of studies and total patients available. There was a tendency towards increased survival in burn patients with acute hypoxemic respiratory failure treated with ECMO. ECMO use of <200 h was correlated with higher survival compared with time >200 h. There was no improvement in survival if ECMO was initiated once the PaO2/FiO2 ratio was <60 [53].

Targeted therapies

Bronchodilators

Bronchodilators have been used in inhalation injury to decrease airflow resistance and improve dynamic compliance. β2-adrenergic agonists such as albuterol and salbutamol have been studied in both sheep and humans. Ovine studies of smoke inhalation injury have shown that both nebulized epinephrine and albuterol decrease airway pressure by smooth muscle relaxation and increase PaO2/FiO2 ratio [54, 55] by limiting the degree of bronchospasm. In addition, epinephrine decreases blood flow to injured/obstructed airways, thus improving V/Q matching.

Muscarinic receptor antagonists such as tiotropium have been studied as well. The parasympathetic response, mediated via muscarinic receptors in the lung, causes smooth muscle constriction within the airways, release of cytokines, and stimulation of submucosal glands [2]. Therefore, by inhibiting these effects, airway pressures are decreased and mucus secretion and cytokine expression are reduced [56]. Jonkam et al. demonstrated in an ovine model that tiotropium improved PaO2/FiO2 ratios and decreased peak airway pressures in the first 24 h following inhalation injury [56].

There is also evidence that both beta agonists and muscarinic receptor antagonists may decrease the host inflammatory response. Additionally, both muscarinic and adrenergic receptors are found on respiratory epithelial gland cells and may impact regeneration and healing following injury. Jacob et al. [57] showed in an ovine model that albuterol/tiotropium resulted in an increase in bronchial ciliated duct and submucosal gland cell proliferation following smoke inhalation and burn injury. In healthy human volunteer and animal studies, epinephrine has been shown to decrease tumor necrosis factor-alpha levels and potentiate IL-10 (a cytokine inhibitor) after lipopolysaccharide stimulation [58, 59].

Mucolytic agents

N-acetylcysteine (NAC) is a powerful mucolytic and may have a role in mitigating ROS damage as it is a precursor of glutathione and a strong reducing agent. While it may aid in breaking up thick airway secretions, it is also an airway irritant and may produce bronchoconstriction; therefore, patients are frequently pre-dosed with a bronchodilating agent [38]. NAC has been proven to be effective in combination with aerosolized heparin for the treatment of inhalation injury in animal studies [60].

Anticoagulants

Inhaled anticoagulants have been used to ameliorate the formation of fibrin casts, which contribute to airway obstruction following inhalation injury. This became a prevalent treatment after Desai et al. [61] demonstrated its utility in a pediatric inhalation injury population. However, in a subsequent retrospective review by Holt et al. [62], a cohort of 150 patients with inhalation injury showed no significant improvement in clinical outcomes in patients treated with inhaled heparin and acetylcysteine. This retrospective study allowed for the institution of nebulized heparin every 4 h for up to 7 days at the attending physician's discretion, and it is unclear whether significant selection bias impacted results [62]. There has been at least one case report of coagulopathy in a patient receiving nebulized heparin and acetylcysteine for inhalation injury [63]. However, Yip et al. [64] demonstrated that nebulized heparin does not increase the risk for pulmonary or systemic bleeding.

Miller et al. [65] found in a retrospective study that patients with inhalation injury who received nebulized heparin and NAC in addition to albuterol experienced a survival benefit with a number needed to treat of 2.73. A multi-center randomized controlled trial by Glas et al. [66] is currently underway to assess nebulized heparin versus placebo in inhalation injury.

Enkhbaatar et al. [67] used a combination of aerosolized heparin and recombinant human antithrombin in an ovine model of cutaneous burn and smoke inhalation. They found the two agents resulted in better lung compliance, less pulmonary edema, and less airway obstruction than controls. Interestingly, neither agent used alone had the same effect [67]. Using this same injury model, they demonstrated that a fibrinolytic agent, tissue plasminogen activator, decreased pulmonary edema, airway obstruction and airway pressures and improved gas exchange [68].

A systematic review of inhaled anticoagulants, including heparin, heparinoids, antithrombin, and fibrinolytics, in inhalation injury confirmed improved survival and decreased morbidity in preclinical and clinical studies [69]. Additionally, anticoagulants may have a systemic role in mitigating host inflammatory response. Combined burn and smoke inhalation injury is associated with myocardial impairment similar to septic cardiomyopathy. Rehberg et al. [70] demonstrated a decrease in the inflammatory changes underlying myocardial dysfunction and improvement in contractility in an ovine model following administration of recombinant human antithrombin.

Anti-inflammatory agents

More specific therapies to mitigate the host inflammatory response and the positive feedback loop introduced through neutrophil migration into the airway and production of ROS and peroxynitrite (ONOO) is an area of intense interest [71]. Neutralization of peroxynitrite with peroxynitrite decomposition catalysts has been demonstrated to be cytoprotective and provide beneficial effects in an ovine model of smoke inhalation injury. Hamahata et al. [72] demonstrated that peroxynitrite decomposition catalyst delivery into the bronchial artery of sheep subjected to burns and inhalation injury attenuated pulmonary damage when compared with a control group that received saline. Additionally, in an animal and human in vitro model of smoke inhalation injury, Perng et al. [25] demonstrated that NOS-mediated activation of the host inflammatory response was attenuated by inhibiting a specific signaling pathway (adenosine-monophosphate-activated protein kinase).

Systemic toxicities

CO has an affinity for hemoglobin 200 to 250 times greater than oxygen and exposure results in hypoxia and ischemia. Unlike inhalation injury, CO has deleterious effects at the level of hemoglobin and more specifically the ability for oxygen delivery. CO acts to displace oxygen from hemoglobin (forming carboxyhemoglobin (COHb)) and binds to cytochrome c oxidase. COHb shifts the oxygen dissociation curve to the left, ultimately leading to decreased oxygen delivery at the tissue level and interfering with cellular respiration at the mitochondrial level [73]. Symptoms of CO toxicity include confusion, stupor, coma, seizures, and myocardial infarction [74]. CO diagnosis requires the use of a Co-oximeter (not available in every blood gas lab), since elevated COHb levels may be present despite normal PaO2 and oxygen saturation readings. Available since 2005, newer, non-invasive CO-oximetry monitors permit more rapid diagnosis [75]. CO poisoning is associated with an increased risk of mortality even at long-term follow-up (median of 7.6 years) [74]. Complications of CO poisoning include persistent and delayed neurologic sequelae and myocardial injury, as well as functional effects on leukocytes, platelets, and vascular endothelium [73]. Treatment of CO poisoning involves providing 100 % oxygen, which shortens the half-life of COHb to about 45 min.

Hyperbaric oxygen therapy (HBO) has been used to treat CO poisoning and can further reduce the COHb half-life to about 20 min. The benefits of HBO were evident in a study of 75 patients with acute CO poisoning. Three treatment sessions were administered within 24 h and neuropsychological tests were administered at various points throughout the study. They found the rates of cognitive sequelae were reduced at 6 weeks and 12 months after CO poisoning in patients with three HBO sessions [76]. It should be pointed out that the theoretical basis for HBO up to 24 h after exposure is to facilitate the clearance of CO from cytochrome c oxidase in the brain, rather than to increase its clearance from hemoglobin in the blood. Logistical factors have limited the utilization of HBO. A systematic review found that not enough evidence exists at this point to determine definitively whether HBO reduces adverse neurologic outcomes after CO poisoning [77]. Continued advancements in HBO technology combined with increased ICU accessibility will likely result in the generation of more clinical studies in this area.

The gaseous form of cyanide, hydrogen cyanide (HCN), is formed in fire atmospheres from the thermal decomposition of nitrogen-containing polymers, both natural (wool, silk, and paper), and synthetic (nylon and polyvinyl chloride). The significance of HCN in fire environments is unclear [11]. The lack of a rapid and reliable test to detect cyanide poisoning limits our understanding of the role of HCN in inhalation injury [78]. Additionally, symptoms can mimic CO poisoning. Dumestre et al. [79] found that most burn centers do not test for cyanide poisoning on admission and do not administer an antidote on the basis of clinical suspicion alone. Lactate has been suggested as a marker for severity of cyanide poisoning without other comorbidities [80], but its role in inhalation injury is less clear in a population at risk for CO poisoning and with coexisting hypovolemic shock. Hydroxocobalamin, the most commonly available antidote (sold as Cyanokit®), binds to HCN to form cyanocobalamin, which is nontoxic and excreted in the urine. The standard dose of 5 g is infused intravenously over 15 min. A second dose of 5 g can be administered in patients with severe toxicity or poor clinical response. It is generally regarded as safe. Red discoloration of the skin and urine is common, which may interfere with colorimetric assays.

Sodium nitrite (300 mg) and sodium thiosulfate (12.5 g) are also commercially available (sold as Nithiodote™). Prior to 2007, when hydroxocobalamin became available, sodium nitrite and sodium thiosulfate were used primarily for cyanide poisoning despite limited data as to their efficacy. In 2012, Bebarta et al. [81] evaluated sodium thiosulfate versus hydroxocobalamin in a swine model of severe cyanide poisoning. They found that sodium thiosulfate failed to reverse cyanide-induced cardiovascular collapse. Further, sodium thiosulfate was not found to be effective when added to hydroxocobalamin. Hydroxocobalamin alone was found to be effective for severe cyanide toxicity. Treatment with nitrites carries significant risk of hypotension and methemoglobinemia, which can further jeopardize tissue oxygen delivery.

Complications from inhalation injuryInhalation injury can be divided into anatomic levels and the mechanism of injury - direct thermal injury to the upper airways or chemical injury to the subglottic region and tracheobronchial tree [8284]. The associated complications vary with the level of injury and are also effected by intubation, infection, and chronic inflammation [82]. In addition, the complications from injury may be acute or delayed. Pneumonia and airway obstruction are early complications of inhalation injury and have been well described in the literature [4, 8]. However, there is a paucity of data on the long-term or delayed complications from inhalation injury [84].

Pneumonia

The most common complication following inhalation injury is respiratory tract infection [85]. Thermal injury activates the host inflammatory response which, when coupled with direct pulmonary injury, places the respiratory system at risk for infection. There is also evidence inhalation injury damages ciliated cells and causes them to detach from the airway epithelium [86]. Coupled with the exfoliation of airway epithelium by chemical irritation, the loss of ciliated cells impairs pulmonary immune function [85, 86]. Surfactant production is also impaired [87] as is mucociliary transport secondary to damage to airway epithelium [88]. The development of respiratory tract infection is also effected by decreased function of pulmonary macrophages [89]. Once the diagnosis of pneumonia is made, empiric antibiotics should be immediately administered. The antibiotic regimen should then be tailored based on the final sputum culture.

At this institution, 1,058 burn patients were evaluated with 35 % diagnosed with inhalation injury via bronchoscopy or 133Xenon lung scan [8]. Of these patients, 38 % developed pneumonia compared with 8.8 % in those without inhalation injury. These authors reported an estimated 20 % increase in mortality with burns and concomitant inhalation injury; mortality increased to 60 % with the development of pneumonia. They found inhalation injury and pneumonia to be independent risk factors for mortality [8].

Airway obstruction

With direct injury to airway epithelium and fluid shifts, upper airway obstruction and pulmonary edema can occur [83]. Airway obstruction is further exacerbated by large fluid resuscitations and should be avoided [83]. Approximately one-third to one-fifth of patients with inhalation injury suffer from acute airway obstruction due to injury to supraglottic structures [38]. These patients require a secure airway either by intubation or tracheostomy [90]. Musosal edema usually peaks around 24 h post-burn and slowly improves over the following several days [90, 91].

From intubation, certain acute complications are known - barotrauma and suction-related injuries - which place the patient more at risk for hospital-acquired pneumonia [90]. Delayed consequences of intubation include tracheomalacia, subglottic stenosis, or innominate fistula [38, 43, 90, 92]. Complications associated with tracheostomies include bleeding, tube malposition, tracheal ulcerations, and tracheitis [91].

Subglottic stenosis and other complications

Direct thermal injury below the vocal cords is unusual given the heat dissipation that occurs in the upper airways [93]. It is the particulate matter from the smoke inhalation and inhalation of steam that contributes significantly to the inflammatory cascade below the larynx [84, 91, 93, 94] and the formation of scar tissue or polyps.

Endobronchial polyps have been reported as both acute and delayed consequences of inhalation injury [84]. The etiology of polyps has been attributed to the epithelialization and fibrous replacement of granulation tissue after damage to the mucosal surfaces. Prevalence is unknown and development can be acute or delayed [84].

A retrospective review by Yang et al. [95] evaluated the incidence of tracheal stenosis in 1,878 burn patients. They found 0.36 % (seven patients) developed tracheal stenosis with five of them having FOB-confirmed inhalation injury (5.5 %). The average time to development was 7 months post-burn. Six patients required intubation for either respiratory distress or prophylaxis. They found prolonged intubation, the presence of inhalation injury, repeated intubates, and neck scar contractures impacted the development of tracheal stenosis [95]. Given the delayed development of stenosis, patients are at risk even after discharge and the true rate is unknown as patients can be symptom free. Other studies report a higher rate of tracheal stenosis in patients with inhalation injury (24 % [96] and 53 % [97]), and predominates in those who underwent intubation [98].

Other complications associated with inhalation injury are bronchiectasis [82, 99, 100], bronchiolitis obliterans [100], vocal cord fixation or fusion [82, 101], and dysphonia [102]. In order to identify and monitor the development of these complications, long-term follow-up (pulmonary function testing and FOB) is necessary [82, 98].

Conclusion

Inhalation injury remains a significant cause of morbidity and mortality in thermally injured patients. Treatment of inhalation injury remains largely supportive. Recent research has led to substantial gains in the understanding of the molecular pathophysiology of inhalation injury. These advances as well as preclinical studies on targeted therapies provide hope for reversal of specific mechanisms of morbidity and improvement in outcomes.

Abbreviations

APRV: 

Airway pressure release ventilation

ARDS: 

Acute respiratory distress syndrome

CO: 

Carbon monoxide

COHb: 

Carboxyhemoglobin

CT: 

Computed tomography

ECMO: 

Extracorporeal membrane oxygenation

FiO2

Fraction of inspired oxygen

FOB: 

Fiberoptic bronchoscopy

HBO: 

Hyperbaric oxygen therapy

HCN: 

Hydrogen cyanide

HFPV: 

High-frequency percussive ventilation

HTV: 

High tidal volume

IL: 

Interleukin

IL-1RA: 

IL-1 Receptor antagonist

LTV: 

Low tidal volume

NAC: 

N-acetylcysteine

NOS: 

Nitric oxide synthase

PaO2

Arterial partial pressure of oxygen

RADS: 

Radiologist’s score

ROS: 

Reactive oxygen species

Declarations

Acknowledgments

This research was supported in part by appointment of one of the authors (LCC) to the Knowledge Preservation Program at the US Army Institute of Surgical Research, administered by the Oak Ridge Institute for Science and Education through an interagency agreement between the US Department of Energy and the US Army Medical Research and Material Command. The opinions or assertions contained herein are the private views of the authors and are not to be construed as official or as reflecting the views of the Department of the Army, Department of the Air Force, or the Department of Defense.

Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

Authors’ Affiliations

(1)
Department of Surgery, Walter Reed National Military Medical Center
(2)
Department of General Surgery, San Antonio Military Medical Center
(3)
Department of Medicine, San Antonio Military Medical Center
(4)
United States Army Institute of Surgical Research
(5)
Department of Surgery, Uniformed Services University of the Health Sciences

References

  1. Albright JM, Davis CS, Bird MD, Ramirez L, Kim H, Burnham EL, et al. The acute pulmonary inflammatory response to the graded severity of smoke inhalation injury. Crit Care Med. 2012;40:1113–21.PubMed CentralView ArticlePubMedGoogle Scholar
  2. Dries DJ, Endorf FW. Inhalation injury: epidemiology, pathology, treatment strategies. Scand J Trauma Resusc Emerg Med. 2013;21:31.PubMed CentralView ArticlePubMedGoogle Scholar
  3. Endorf FW, Gamelli RL. Inhalation injury, pulmonary perturbations, and fluid resuscitation. J Burn Care Res. 2007;28:80–3. doi:https://doi.org/10.1097/bcr.0b013e31802c889f.View ArticlePubMedGoogle Scholar
  4. Palmieri TL. Inhalation injury: research progress and needs. J Burn Care Res. 2007;28:549–54. doi:https://doi.org/10.1097/bcr.0b013e318093def0.View ArticlePubMedGoogle Scholar
  5. You K, Yang HT, Kym D, Yoon J, Haejun Y, Cho YS, et al. Inhalation injury in burn patients: establishing the link between diagnosis and prognosis. Burns. 2014;40:1470–5. doi:https://doi.org/10.1016/j.burns.2014.09.015.View ArticlePubMedGoogle Scholar
  6. El-Helbawy RH, Ghareeb FM. Inhalation injury as a prognostic factor for mortality in burn patients. Ann Burns Fire Disasters. 2011;24:82–8.PubMed CentralPubMedGoogle Scholar
  7. Smith DL, Cairns BA, Ramadan F, Dalston JS, Fakhry SM, Rutledge R, 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.View ArticlePubMedGoogle Scholar
  8. Shirani KZ, Pruitt Jr BA, Mason Jr AD. The influence of inhalation injury and pneumonia on burn mortality. Ann Surg. 1987;205:82–7.PubMed CentralView ArticlePubMedGoogle Scholar
  9. Moritz AR, Henriques FC, McLean R. The effects of inhaled heat on the air passages and lungs: an experimental investigation. Am J Pathol. 1945;21:311–31.PubMed CentralPubMedGoogle Scholar
  10. Petajan JH, Voorhees KJ, Packham SC, Baldwin RC, Einhorn IN, Grunnet ML, et al. Extreme toxicity from combustion products of a fire-retarded polyurethane foam. Science. 1975;187:742–4.View ArticlePubMedGoogle Scholar
  11. Gann RG, Averill JD, Butler KM, Jones WW, Mulholland GW, Neviaser JL, et al. International Study of the Sublethal Effects of Fire Smoke on Survivability and Health (SEFS): Phase I Final Report. NIST Technical Note 1439. 2001. http://fire.nist.gov/bfrlpubs/fire01/PDF/f01080.pdf.
  12. Fontan JJ, Cortright DN, Krause JE, Velloff CR, Karpitskyi VV, Carver Jr TW, et al. Substance P and neurokinin-1 receptor expression by intrinsic airway neurons in the rat. Am J Physiol Lung Cell Mol Physiol. 2000;278:L344–55.PubMedGoogle Scholar
  13. Lange M, Enkhbaatar P, Traber DL, Cox RA, Jacob S, Mathew BP, et al. Role of calcitonin gene-related peptide (CGRP) in ovine burn and smoke inhalation injury. J Appl Physiol. 2009;107:176–84. doi:https://doi.org/10.1152/japplphysiol.00094.2009.PubMed CentralView ArticlePubMedGoogle Scholar
  14. Kraneveld AD, Nijkamp FP. Tachykinins and neuro-immune interactions in asthma. Int Immunopharmacol. 2001;1:1629–50.View ArticlePubMedGoogle Scholar
  15. Sureshbabu A, Bhandari V. Targeting mitochondrial dysfunction in lung diseases: emphasis on mitophagy. Front Physiol. 2013;4:384. doi:https://doi.org/10.3389/fphys.2013.00384.PubMed CentralView ArticlePubMedGoogle Scholar
  16. Midde KK, Batchinsky AI, Cancio LC, Shetty S, Komissarov AA, Florova G, et al. Wood bark smoke induces lung and pleural plasminogen activator inhibitor 1 and stabilizes its mRNA in porcine lung cells. Shock. 2011;36:128–37. doi:https://doi.org/10.1097/SHK.0b013e31821d60a4.PubMed CentralView ArticlePubMedGoogle Scholar
  17. Murakami K, Traber DL. Pathophysiological basis of smoke inhalation injury. News Physiol Sci. 2003;18:125–9.PubMedGoogle Scholar
  18. Morita N, Enkhbaatar P, Maybauer DM, Maybauer MO, Westphal M, Murakami K, et al. Impact of bronchial circulation on bronchial exudates following combined burn and smoke inhalation injury in sheep. Burns. 2011;37:465–73. doi:https://doi.org/10.1016/j.burns.2010.11.005.PubMed CentralView ArticlePubMedGoogle Scholar
  19. Cancio LC, Batchinsky AI, Dubick MA, Park MS, Black IH, Gomez R, et al. Inhalation injury: pathophysiology and clinical care proceedings of a symposium conducted at the Trauma Institute of San Antonio, San Antonio, TX, USA on 28 March 2006. Burns. 2007;33:681–92. doi:https://doi.org/10.1016/j.burns.2006.11.009.View ArticlePubMedGoogle Scholar
  20. Traber DLHD, Enkhbaatar P, Maybauer MO, Maybauer DM. The pathophysiology of inhalation injury. In: Herndon DN, editor. Total burn care. 2nd ed. Philadelphia: Saunders; 2012. p. 219–28.View ArticleGoogle Scholar
  21. Buehner M, Pamplin J, Studer L, Hughes RL, King BT, Graybill JC, et al. Oxalate nephropathy after continuous infusion of high-dose vitamin C as an adjunct to burn resuscitation. J Burn Care Res. 2015. doi:https://doi.org/10.1097/bcr.0000000000000233.PubMedGoogle Scholar
  22. Davis CS, Janus SE, Mosier MJ, Carter SR, Gibbs JT, Ramirez L, et al. Inhalation injury severity and systemic immune perturbations in burned adults. Ann Surg. 2013;257:1137–46. doi:https://doi.org/10.1097/SLA.0b013e318275f424.PubMed CentralView ArticlePubMedGoogle Scholar
  23. Weyker PD, Webb CA, Kiamanesh D, Flynn BC. Lung ischemia reperfusion injury: a bench-to-bedside review. Semin Cardiothorac Vasc Anesth. 2013;17:28–43. doi:https://doi.org/10.1177/1089253212458329.View ArticlePubMedGoogle Scholar
  24. Park MS, Cancio LC, Jordan BS, Brinkley WW, Rivera VR, Dubick MA. Assessment of oxidative stress in lungs from sheep after inhalation of wood smoke. Toxicology. 2004;195:97–112.View ArticlePubMedGoogle Scholar
  25. Perng DW, Chang TM, Wang JY, Lee CC, Lu SH, Shyue SK, et al. Inflammatory role of AMP-activated protein kinase signaling in an experimental model of toxic smoke inhalation injury. Crit Care Med. 2013;41:120–32. doi:https://doi.org/10.1097/CCM.0b013e318265f653.View ArticlePubMedGoogle Scholar
  26. Espinoza LA, Smulson ME, Chen Z. Prolonged poly(ADP-ribose) polymerase-1 activity regulates JP-8-induced sustained cytokine expression in alveolar macrophages. Free Radic Biol Med. 2007;42:1430–40. doi:https://doi.org/10.1016/j.freeradbiomed.2007.01.043.View ArticlePubMedGoogle Scholar
  27. Lange M, Connelly R, Traber DL, Hamahata A, Nakano Y, Esechie A, et al. Time course of nitric oxide synthases, nitrosative stress, and poly(ADP ribosylation) in an ovine sepsis model. Crit Care. 2010;14:R129. doi:https://doi.org/10.1186/cc9097.PubMed CentralView ArticlePubMedGoogle Scholar
  28. Hassan Z, Wong JK, Bush J, Bayat A, Dunn KW. Assessing the severity of inhalation injuries in adults. Burns. 2010;36:212–6. doi:https://doi.org/10.1016/j.burns.2009.06.205.View ArticlePubMedGoogle Scholar
  29. Park MS, Cancio LC, Batchinsky AI, McCarthy MJ, Jordan BS, Brinkley WW, et al. Assessment of severity of ovine smoke inhalation injury by analysis of computed tomographic scans. J Trauma. 2003;55:417–27. doi:https://doi.org/10.1097/01.ta.0000083609.24440.7f. discussion 427–9.View ArticlePubMedGoogle Scholar
  30. Woodson LC. Diagnosis and grading of inhalation injury. J Burn Care Res. 2009;30:143–5. doi:https://doi.org/10.1097/BCR.0b013e3181923b71.View ArticlePubMedGoogle Scholar
  31. Mosier MJ, Pham TN, Park DR, Simmons J, Klein MB, Gibran NS. Predictive value of bronchoscopy in assessing the severity of inhalation injury. J Burn Care Res. 2012;33:65–73. doi:https://doi.org/10.1097/BCR.0b013e318234d92f.View ArticlePubMedGoogle Scholar
  32. Ryan CM, Fagan SP, Goverman J, Sheridan RL. Grading inhalation injury by admission bronchoscopy. Crit Care Med. 2012;40:1345–6. doi:https://doi.org/10.1097/CCM.0b013e31823c8b2f.View ArticlePubMedGoogle Scholar
  33. Cancio LC, Galvez Jr E, Turner CE, Kypreos NG, Parker A, Holcomb JB. Base deficit and alveolar-arterial gradient during resuscitation contribute independently but modestly to the prediction of mortality after burn injury. J Burn Care Res. 2006;27:289–96. doi:https://doi.org/10.1097/01.bcr.0000216457.25875.f4. discussion 296–7.View ArticlePubMedGoogle Scholar
  34. Oh JS, Chung KK, Allen A, Batchinsky AI, Huzar T, King BT, et al. Admission chest CT complements fiberoptic bronchoscopy in prediction of adverse outcomes in thermally injured patients. J Burn Care Res. 2012;33:532–8. doi:https://doi.org/10.1097/BCR.0b013e318237455f.View ArticlePubMedGoogle Scholar
  35. Yamamura H, Kaga S, Kaneda K, Mizobata Y. Chest computed tomography performed on admission helps predict the severity of smoke-inhalation injury. Crit Care. 2013;17:R95. doi:https://doi.org/10.1186/cc12740.PubMed CentralView ArticlePubMedGoogle Scholar
  36. Kwon HP, Zanders TB, Regn DD, Burkett SE, Ward JA, Nguyen R, et al. Comparison of virtual bronchoscopy to fiber-optic bronchoscopy for assessment of inhalation injury severity. Burns. 2014;40:1308–15. doi:https://doi.org/10.1016/j.burns.2014.06.007.View ArticlePubMedGoogle Scholar
  37. Putman CE, Loke J, Matthay RA, Ravin CE. Radiographic manifestations of acute smoke inhalation. AJR Am J Roentgenol. 1977;129:865–70. doi:https://doi.org/10.2214/ajr.129.5.865.View ArticlePubMedGoogle Scholar
  38. Mlcak RP, Suman OE, Herndon DN. Respiratory management of inhalation injury. Burns. 2007;33:2–13. doi:https://doi.org/10.1016/j.burns.2006.07.007.View ArticlePubMedGoogle Scholar
  39. Venus B, Matsuda T, Copiozo JB, Mathru M. Prophylactic intubation and continuous positive airway pressure in the management of inhalation injury in burn victims. Crit Care Med. 1981;9:519–23.View ArticlePubMedGoogle Scholar
  40. Reper P, van Looy K. Chest physiotherapy using intrapulmonary percussive ventilation to treat persistent atelectasis in hypoxic patients after smoke inhalation. Burns. 2013;39:192–3. doi:https://doi.org/10.1016/j.burns.2012.04.015.View ArticlePubMedGoogle Scholar
  41. Mackie DP, van Dehn F, Knape P, Breederveld RS, Boer C. Increase in early mechanical ventilation of burn patients: an effect of current emergency trauma management? J Trauma. 2011;70:611–5. doi:https://doi.org/10.1097/TA.0b013e31821067aa.View ArticlePubMedGoogle Scholar
  42. Mackie DP. Inhalation injury or mechanical ventilation: which is the true killer in burn patients? Burns. 2013;39:1329–30. doi:https://doi.org/10.1016/j.burns.2013.07.006.View ArticlePubMedGoogle Scholar
  43. Fitzpatrick JC, Cioffi Jr WG. Ventilatory support following burns and smoke-inhalation injury. Respir Care Clin N Am. 1997;3:21–49.PubMedGoogle Scholar
  44. Petrucci N, Iacovelli W. Lung protective ventilation strategy for the acute respiratory distress syndrome. Cochrane Database Syst Rev. 2007:Cd003844. doi:https://doi.org/10.1002/14651858.CD003844.pub3.
  45. Cioffi WG, Graves TA, McManus WF, Pruitt Jr BA. High-frequency percussive ventilation in patients with inhalation injury. J Trauma. 1989;29:350–4.View ArticlePubMedGoogle Scholar
  46. Cioffi Jr WG, Rue 3rd LW, Graves TA, McManus WF, Mason Jr AD, Pruitt Jr BA. Prophylactic use of high-frequency percussive ventilation in patients with inhalation injury. Ann Surg. 1991;213:575–80. discussion 580–2.PubMed CentralView ArticlePubMedGoogle Scholar
  47. Hall JJ, Hunt JL, Arnoldo BD, Purdue GF. Use of high-frequency percussive ventilation in inhalation injuries. J Burn Care Res. 2007;28:396–400. doi:https://doi.org/10.1097/bcr.0b013e318053d2d6.View ArticlePubMedGoogle Scholar
  48. Cortiella J, Mlcak R, Herndon D. High frequency percussive ventilation in pediatric patients with inhalation injury. J Burn Care Rehabil. 1999;20:232–5.View ArticlePubMedGoogle Scholar
  49. Chung KK, Wolf SE, Renz EM, Allan PF, Aden JK, Merrill GA, et al. High-frequency percussive ventilation and low tidal volume ventilation in burns: a randomized controlled trial. Crit Care Med. 2010;38:1970–7. doi:https://doi.org/10.1097/CCM.0b013e3181eb9d0b.View ArticlePubMedGoogle Scholar
  50. Sousse LE, Herndon DN, Andersen CR, Ali A, Benjamin NC, Granchi T, 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. doi:https://doi.org/10.1016/j.jamcollsurg.2014.12.028.View ArticlePubMedGoogle Scholar
  51. Batchinsky AI, Burkett SE, Zanders TB, Chung KK, Regn DD, Jordan BS, 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. doi:https://doi.org/10.1097/CCM.0b013e318225b5b3.View ArticlePubMedGoogle Scholar
  52. Hale DF, Cannon JW, Batchinsky AI, Cancio LC, Aden JK, White CE, et al. Prone positioning improves oxygenation in adult burn patients with severe acute respiratory distress syndrome. J Trauma Acute Care Surg. 2012;72:1634–9. doi:https://doi.org/10.1097/TA.0b013e318247cd4f.View ArticlePubMedGoogle Scholar
  53. Asmussen S, Maybauer DM, Fraser JF, Jennings K, George S, Keiralla A, et al. Extracorporeal membrane oxygenation in burn and smoke inhalation injury. Burns. 2013;39:429–35. doi:https://doi.org/10.1016/j.burns.2012.08.006.View ArticlePubMedGoogle Scholar
  54. Lange M, Hamahata A, Traber DL, Cox RA, Kulp GA, Nakano Y, 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. doi:https://doi.org/10.1097/CCM.0b013e318207ec52.View ArticlePubMedGoogle Scholar
  55. Palmieri TL, Enkhbaatar P, Bayliss R, Traber LD, Cox RA, Hawkins HK, 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. doi:https://doi.org/10.1097/01.ccm.0000217215.82821.c5.View ArticlePubMedGoogle Scholar
  56. Jonkam C, Zhu Y, Jacob S, Rehberg S, Kraft E, Hamahata A, et al. Muscarinic receptor antagonist therapy improves acute pulmonary dysfunction after smoke inhalation injury in sheep. Crit Care Med. 2010;38:2339–44. doi:https://doi.org/10.1097/CCM.0b013e3181f8557b.View ArticlePubMedGoogle Scholar
  57. Jacob S, Zhu Y, Jonkam C, Asmussen S, Traber L, Herndon DN, et al. Effect of bronchodilators on bronchial gland cell proliferation after inhalation and burn injury in sheep. J Burn Care Res. 2013;34:386–93. doi:https://doi.org/10.1097/BCR.0b013e31826fc51e.View ArticlePubMedGoogle Scholar
  58. van der Poll T, Coyle SM, Barbosa K, Braxton CC, Lowry SF. Epinephrine inhibits tumor necrosis factor-alpha and potentiates interleukin 10 production during human endotoxemia. J Clin Invest. 1996;97:713–9. doi:https://doi.org/10.1172/jci118469.PubMed CentralView ArticlePubMedGoogle Scholar
  59. Zhang H, Kim YK, Govindarajan A, Baba A, Binnie M, Marco Ranieri V, et al. Effect of adrenoreceptors on endotoxin-induced cytokines and lipid peroxidation in lung explants. Am J Respir Crit Care Med. 1999;160:1703–10. doi:https://doi.org/10.1164/ajrccm.160.5.9903068.View ArticlePubMedGoogle Scholar
  60. Brown M, Desai M, Traber LD, Herndon DN, Traber DL. Dimethylsulfoxide with heparin in the treatment of smoke inhalation injury. J Burn Care Rehabil. 1988;9:22–5.View ArticlePubMedGoogle Scholar
  61. Desai MH, Mlcak R, Richardson J, Nichols R, Herndon DN. Reduction in mortality in pediatric patients with inhalation injury with aerosolized heparin/N-acetylcystine [correction of acetylcystine] therapy. J Burn Care Rehabil. 1998;19:210–2.View ArticlePubMedGoogle Scholar
  62. Holt J, Saffle JR, Morris SE, Cochran A. Use of inhaled heparin/N-acetylcystine in inhalation injury: does it help? J Burn Care Res. 2008;29:192–5. doi:https://doi.org/10.1097/BCR.0b013e31815f596b.PubMedGoogle Scholar
  63. Chopra A, Burkey B, Calaman S. A case report of clinically significant coagulopathy associated with aerosolized heparin and acetylcysteine therapy for inhalation injury. Burns. 2011;37:e73–5. doi:https://doi.org/10.1016/j.burns.2011.07.019.View ArticlePubMedGoogle Scholar
  64. Yip LY, Lim YF, Chan HN. Safety and potential anticoagulant effects of nebulised heparin in burns patients with inhalational injury at Singapore General Hospital Burns Centre. Burns. 2011;37:1154–60. doi:https://doi.org/10.1016/j.burns.2011.07.006.View ArticlePubMedGoogle Scholar
  65. Miller AC, Rivero A, Ziad S, Smith DJ, Elamin EM. Influence of nebulized unfractionated heparin and N-acetylcysteine in acute lung injury after smoke inhalation injury. J Burn Care Res. 2009;30:249–56. doi:https://doi.org/10.1097/BCR.0b013e318198a268.View ArticlePubMedGoogle Scholar
  66. Glas GJ, Muller J, Binnekade JM, Cleffken B, Colpaert K, Dixon B, et al. HEPBURN - investigating the efficacy and safety of nebulized heparin versus placebo in burn patients with inhalation trauma: study protocol for a multi-center randomized controlled trial. Trials. 2014;15:91. doi:https://doi.org/10.1186/1745-6215-15-91.PubMed CentralView ArticlePubMedGoogle Scholar
  67. Enkhbaatar P, Cox RA, Traber LD, Westphal M, Aimalohi E, Morita N, et al. Aerosolized anticoagulants ameliorate acute lung injury in sheep after exposure to burn and smoke inhalation. Crit Care Med. 2007;35:2805–10.View ArticlePubMedGoogle Scholar
  68. Enkhbaatar P, Murakami K, Cox R, Westphal M, Morita N, Brantley K, et al. Aerosolized tissue plasminogen inhibitor improves pulmonary function in sheep with burn and smoke inhalation. Shock. 2004;22:70–5.View ArticlePubMedGoogle Scholar
  69. Miller AC, Elamin EM, Suffredini AF. Inhaled anticoagulation regimens for the treatment of smoke inhalation-associated acute lung injury: a systematic review. Crit Care Med. 2014;42:413–9. doi:https://doi.org/10.1097/CCM.0b013e3182a645e5.PubMed CentralView ArticlePubMedGoogle Scholar
  70. Rehberg S, Yamamoto Y, Bartha E, Sousse LE, Jonkam C, Zhu Y, et al. Antithrombin attenuates myocardial dysfunction and reverses systemic fluid accumulation following burn and smoke inhalation injury: a randomized, controlled, experimental study. Crit Care. 2013;17:R86. doi:https://doi.org/10.1186/cc12712.PubMed CentralView ArticlePubMedGoogle Scholar
  71. Lange M, Szabo C, Enkhbaatar P, Connelly R, Horvath E, Hamahata A, et al. Beneficial pulmonary effects of a metalloporphyrinic peroxynitrite decomposition catalyst in burn and smoke inhalation injury. Am J Physiol Lung Cell Mol Physiol. 2011;300:L167–75. doi:https://doi.org/10.1152/ajplung.00277.2010.PubMed CentralView ArticlePubMedGoogle Scholar
  72. Hamahata A, Enkhbaatar P, Lange M, Yamaki T, Nakazawa H, Nozaki M, et al. Administration of a peroxynitrite decomposition catalyst into the bronchial artery attenuates pulmonary dysfunction after smoke inhalation and burn injury in sheep. Shock. 2012;38:543–8. doi:https://doi.org/10.1097/SHK.0b013e31826e9c54.View ArticlePubMedGoogle Scholar
  73. Kealey GP. Carbon monoxide toxicity. J Burn Care Res. 2009;30:146–7. doi:https://doi.org/10.1097/BCR.0b013e3181923b81.View ArticlePubMedGoogle Scholar
  74. Henry CR, Satran D, Lindgren B, Adkinson C, Nicholson CI, Henry TD. Myocardial injury and long-term mortality following moderate to severe carbon monoxide poisoning. JAMA. 2006;295:398–402. doi:https://doi.org/10.1001/jama.295.4.398.View ArticlePubMedGoogle Scholar
  75. Hampson NB. Noninvasive pulse CO-oximetry expedites evaluation and management of patients with carbon monoxide poisoning. Am J Emerg Med. 2012;30:2021–4. doi:https://doi.org/10.1016/j.ajem.2012.03.026.View ArticlePubMedGoogle Scholar
  76. Weaver LK. Hyperbaric oxygen therapy for carbon monoxide poisoning. Undersea Hyperb Med. 2014;41:339–54.PubMedGoogle Scholar
  77. Buckley NA, Juurlink DN, Isbister G, Bennett MH, Lavonas EJ. Hyperbaric oxygen for carbon monoxide poisoning. Cochrane Database Syst Rev. 2011:Cd002041. doi:https://doi.org/10.1002/14651858.CD002041.pub3.
  78. Erdman AR. Is hydroxocobalamin safe and effective for smoke inhalation? Searching for guidance in the haze. Ann Emerg Med. 2007;49:814–6. doi:https://doi.org/10.1016/j.annemergmed.2007.03.006.View ArticlePubMedGoogle Scholar
  79. Dumestre D, Nickerson D. Use of cyanide antidotes in burn patients with suspected inhalation injuries in North America: a cross-sectional survey. J Burn Care Res. 2014;35:e112–7. doi:https://doi.org/10.1097/BCR.0b013e31829b3868.View ArticlePubMedGoogle Scholar
  80. Baud FJ, Borron SW, Megarbane B, Trout H, Lapostolle F, Vicaut E, et al. Value of lactic acidosis in the assessment of the severity of acute cyanide poisoning. Crit Care Med. 2002;30:2044–50. doi:https://doi.org/10.1097/01.ccm.0000026325.65944.7d.View ArticlePubMedGoogle Scholar
  81. Bebarta VS, Pitotti RL, Dixon P, Lairet JR, Bush A, Tanen DA. Hydroxocobalamin versus sodium thiosulfate for the treatment of acute cyanide toxicity in a swine (Sus scrofa) model. Ann Emerg Med. 2012;59:532–9. doi:https://doi.org/10.1016/j.annemergmed.2012.01.022.View ArticlePubMedGoogle Scholar
  82. Cancio LC. Airway management and smoke inhalation injury in the burn patient. Clin Plastic Surg. 2009;36:555–67. doi:https://doi.org/10.1016/j.cps.2009.05.013.View ArticleGoogle Scholar
  83. Moylan JA, Chan CK. Inhalation injury - an increasing problem. Ann Surg. 1978;188:34–7.PubMed CentralView ArticlePubMedGoogle Scholar
  84. Shin B, Kim M, Yoo H, Kim SJ, Lee JE, Jeon K. Tracheobronchial polyps following thermal inhalation injury. Tuberc Respir Dis (Seoul). 2014;76:237–9. doi:https://doi.org/10.4046/trd.2014.76.5.237.View ArticleGoogle Scholar
  85. Pruitt Jr BA, Erickson DR, Morris A. Progressive pulmonary insufficiency and other pulmonary complications of thermal injury. J Trauma. 1975;15:369–79.View ArticlePubMedGoogle Scholar
  86. Jacob S, Kraft R, Zhu Y, Jacob RK, Herndon DN, Traber DL, et al. Acute secretory cell toxicity and epithelial exfoliation after smoke inhalation injury in sheep: an electron and light microscopic study. Toxicol Mech Methods. 2010;20:504–9. doi:https://doi.org/10.3109/15376516.2010.511302.View ArticlePubMedGoogle Scholar
  87. Nieman GF, Clark Jr WR, Wax SD, Webb SR. The effect of smoke inhalation on pulmonary surfactant. Ann Surg. 1980;191:171–81.PubMed CentralView ArticlePubMedGoogle Scholar
  88. Loke J, Paul E, Virgulto JA, Smith GJ. Rabbit lung after acute smoke inhalation. Cellular responses and scanning electron microscopy. Arch Surg. 1984;119:956–9.View ArticlePubMedGoogle Scholar
  89. Sherwin RP, Richters V. Lung capillary permeability. Nitrogen dioxide exposure and leakage of tritiated serum. Arch Internal Med. 1971;128:61–8.View ArticleGoogle Scholar
  90. Cochran A. Inhalation injury and endotracheal intubation. J Burn Care Res. 2009;30:190–1. doi:https://doi.org/10.1097/BCR.0b013e3181923eb4.View ArticlePubMedGoogle Scholar
  91. Carrougher GJ. Inhalation injury. AACN Clin Issues Crit Care Nursing. 1993;4:367–77.Google Scholar
  92. Kadilak PR, Vanasse S, Sheridan RL. Favorable short- and long-term outcomes of prolonged translaryngeal intubation in critically ill children. J Burn Care Rehabil. 2004;25:262–5.View ArticlePubMedGoogle Scholar
  93. Toon MH, Maybauer MO, Greenwood JE, Maybauer DM, Fraser JF. Management of acute smoke inhalation injury. Crit Care Resusc. 2010;12:53–61.PubMedGoogle Scholar
  94. Fang-Gang N, Yang C, Yu-Xuan Q, Yan-Hua R, Wei-Li D, Cheng W, et al. Laryngeal morphologic changes and epidemiology in patients with inhalation injury: a retrospective study. Burns. 2015. doi:https://doi.org/10.1016/j.burns.2015.02.003.PubMedGoogle Scholar
  95. Yang JY, Yang WG, Chang LY, Chuang SS. Symptomatic tracheal stenosis in burns. Burns. 1999;25:72–80.View ArticlePubMedGoogle Scholar
  96. Jones WG, Madden M, Finkelstein J, Yurt RW, Goodwin CW. Tracheostomies in burn patients. Ann Surg. 1989;209:471–4.PubMed CentralView ArticlePubMedGoogle Scholar
  97. Lund T, Goodwin CW, McManus WF, Shirani KZ, Stallings RJ, Mason Jr AD, et al. Upper airway sequelae in burn patients requiring endotracheal intubation or tracheostomy. Ann Surg. 1985;201:374–82.PubMed CentralView ArticlePubMedGoogle Scholar
  98. Gaissert HA, Lofgren RH, Grillo HC. Upper airway compromise after inhalation injury. Complex strictures of the larynx and trachea and their management. Ann Surg. 1993;218:672–8.PubMed CentralView ArticlePubMedGoogle Scholar
  99. Mahut B, Delacourt C, de Blic J, Mani TM, Scheinmann P. Bronchiectasis in a child after acrolein inhalation. Chest. 1993;104:1286–7.View ArticlePubMedGoogle Scholar
  100. Tasaka S, Kanazawa M, Mori M, Fujishima S, Ishizaka A, Yamasawa F, et al. Long-term course of bronchiectasis and bronchiolitis obliterans as late complication of smoke inhalation. Respiration. 1995;62:40–2.View ArticlePubMedGoogle Scholar
  101. Cobley TD, Hart WJ, Baldwin DL, Burd DA. Complete fusion of the vocal cords; an unusual case. Burns. 1999;25:361–3.View ArticlePubMedGoogle Scholar
  102. Casper JK, Clark WR, Kelley RT, Colton RH. Laryngeal and phonatory status after burn/inhalation injury: a long term follow-up study. J Burn Care Rehabil. 2002;23:235–43. doi:https://doi.org/10.1097/01.bcr.0000020446.71916.f9.View ArticlePubMedGoogle Scholar

Copyright

© Walker et al. 2015