Inhalation Injury: Difference between revisions

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== Introduction ==
== Introduction ==
[[File:Respiratory System.png|thumb]]
[[File:Respiratory System.png|thumb]]
Inhalation injury is one of the most challenging injuries for [[Burns Overview|burn]] care providers, since it is one of the classic determinants of mortality from severe burn injury; other determinants include age, extent of injury, and delays of resuscitation.<ref name=":0">Jones SW, Williams FN, Cairns BA, Cartotto R. Inhalation injury: pathophysiology, diagnosis, and treatment. Clinics in plastic surgery. 2017 Jul 1;44(3):505-11.</ref> It refers to pulmonary injury resulting from inhalation of smoke or chemical products of combustion.<ref name=":1">Dries and EndorfScandinavian Journal of Trauma, Resuscitation and Emergency Medicine2013,21:31</ref>
Inhalation injury happens to be one of the most challenging injuries for [[Burns Overview|burn]] care providers. This is because it is one of the classic determinants of mortality that occurs after severe burn injury. The other determinants are age, extent of injury, as well as delay in resuscitation.<ref name=":0">Jones SW, Williams FN, Cairns BA, Cartotto R. Inhalation injury: pathophysiology, diagnosis, and treatment. Clinics in plastic surgery. 2017 Jul 1;44(3):505-11.</ref> Inhalation injury refers to pulmonary injury resulting from inhalation of smoke or chemical products of combustion.<ref name=":1">Dries and EndorfScandinavian Journal of Trauma, Resuscitation and Emergency Medicine2013,21:31</ref>


Inhalation injury results in localized damage through direct cellular damage, alterations to regional blood flow and perfusion, airway obstruction, and toxin and pro-inflammatory cytokine release.<ref name=":2">Kadri SS, Miller AC, Hohmann S, Bonne S, Nielsen C, Wells C, Gruver C, Quraishi SA, Sun J, Cai R, Morris PE. Risk factors for in-hospital mortality in smoke inhalation-associated acute lung injury: data from 68 United States hospitals. Chest. 2016 Dec 1;150(6):1260-8.</ref><ref>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. [PubMed: 24986596]</ref> Inhalation injuries results in incapacitation of mucociliary clearance and impairment of alveolar macrophages.<ref>Al Ashry HS, Mansour G, Kalil AC, Walters RW, Vivekanandan R. Incidence of ventilator associated pneumonia in burn patients with inhalation injury treated with high frequency percussive ventilation versus volume control ventilation: A systematic review. Burns. 2016 Sep 1;42(6):1193-200.</ref> It predisposes patients to bacterial infection, specifically and primarily pneumonia, a leading cause of death for burn patients.<ref name=":3">Mlcak RP, Suman OE, Herndon DN. Respiratory management of inhalation injury. burns. 2007 Feb 1;33(1):2-13.</ref><ref>Pruitt BA, McManus AT. The changing epidemiology of infection in burn patients. World journal of surgery. 1992 Jan 1;16(1):57-67.</ref>
Inhalation injury causes localized damage by direct cellular damage, disruptions in regional blood flow and perfusion, obstruction of the airways, and toxin and pro-inflammatory cytokine release.<ref name=":2">Kadri SS, Miller AC, Hohmann S, Bonne S, Nielsen C, Wells C, Gruver C, Quraishi SA, Sun J, Cai R, Morris PE. Risk factors for in-hospital mortality in smoke inhalation-associated acute lung injury: data from 68 United States hospitals. Chest. 2016 Dec 1;150(6):1260-8.</ref><ref>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. [PubMed: 24986596]</ref> Inhalation injuries also causes reduced functionality of mucociliary clearance and weakening of alveolar macrophages.<ref>Al Ashry HS, Mansour G, Kalil AC, Walters RW, Vivekanandan R. Incidence of ventilator associated pneumonia in burn patients with inhalation injury treated with high frequency percussive ventilation versus volume control ventilation: A systematic review. Burns. 2016 Sep 1;42(6):1193-200.</ref> With this, patient is placed at a high risk of bacterial infection, especially pneumonia, which is one of the top causes of death for burn patients.<ref name=":3">Mlcak RP, Suman OE, Herndon DN. Respiratory management of inhalation injury. burns. 2007 Feb 1;33(1):2-13.</ref><ref>Pruitt BA, McManus AT. The changing epidemiology of infection in burn patients. World journal of surgery. 1992 Jan 1;16(1):57-67.</ref>


== Epidemiology ==
== Epidemiology ==
Inhalation injury usually accompanies up to one-third of all burn injuries and it accounts to up to 90% of all burn-related mortality.<ref name=":2" /><ref>Tan A, Smailes S, Friebel T, Magdum A, Frew Q, El-Muttardi N, Dziewulski P. Smoke inhalation increases intensive care requirements and morbidity in paediatric burns. Burns. 2016 Aug 1;42(5):1111-5.</ref> Up to 10.3% of burn patients were reported by the National Burn Repository of the American Burn Association to have concomitant inhalation injury.<ref>Burn Incidence Fact Sheet. American Burn Association; 2016 National Burn Repository. American Burn Association; 2017.</ref> As such, 1 in 10 burn patients surviving to admission will have the inhalation injury with the respective increase in the mortality rate.<ref>Foncerrada G, Culnan DM, Capek KD, González-Trejo S, Cambiaso-Daniel J, Woodson LC, Herndon DN, Finnerty CC, Lee JO. Inhalation injury in the burned patient. Annals of plastic surgery. 2018 Mar;80(3 Suppl 2):S98.</ref>
Inhalation injury is recorded in about one-third of all burn injuries and it is responsible for about 90% of all burn-related mortality.<ref name=":2" /><ref>Tan A, Smailes S, Friebel T, Magdum A, Frew Q, El-Muttardi N, Dziewulski P. Smoke inhalation increases intensive care requirements and morbidity in paediatric burns. Burns. 2016 Aug 1;42(5):1111-5.</ref> The National Burn Repository of the American Burn Association reported up to 10.3% of burn patients to have accompanying inhalation injury.<ref>Burn Incidence Fact Sheet. American Burn Association; 2016 National Burn Repository. American Burn Association; 2017.</ref> Thus, 1 in 10 burn patients that survive to admission will have the inhalation injury and a corresponding increase in the mortality rate.<ref>Foncerrada G, Culnan DM, Capek KD, González-Trejo S, Cambiaso-Daniel J, Woodson LC, Herndon DN, Finnerty CC, Lee JO. Inhalation injury in the burned patient. Annals of plastic surgery. 2018 Mar;80(3 Suppl 2):S98.</ref>


== Classes ==
== Classes ==
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=== Heat Injury to the Upper Airway ===
=== Heat Injury to the Upper Airway ===
When the temperature of the air in a room containing a fire reaches 1000°F, injury is caused to airway structures above the carina due to the combination of efficient heat dissipation in the upper airway, low heat capacity of air and reflex closure of the larynx.<ref>Pruitt Jr BA, Flemma RJ, DiVincenti FC, Foley FD, Mason Jr AD, Young Jr WG. Pulmonary complications in burn patients: a comparative study of 697 patients. The Journal of thoracic and cardiovascular surgery. 1970 Jan 1;59(1):7-20.</ref>
When the room air temperature reaches 1000°F after a fire outbreak, injury is results to structures of the airway above the carina. This results due to the combination of efficient heat dissipation in the upper airway, low heat capacity of air and reflex closure of the larynx.<ref>Pruitt Jr BA, Flemma RJ, DiVincenti FC, Foley FD, Mason Jr AD, Young Jr WG. Pulmonary complications in burn patients: a comparative study of 697 patients. The Journal of thoracic and cardiovascular surgery. 1970 Jan 1;59(1):7-20.</ref>


Injury to these airway structures may cause massive swelling of the tongue, epiglottis, and aryepiglottic folds with obstruction. Airway swelling develops over a matter of hours as fluid resuscitation is ongoing. Initial evaluation is not a good indicator of the severity of obstruction that may occur later.<ref>Palmieri TL. Inhalation injury: research progress and needs. Journal of burn care & research. 2007 Jul 1;28(4):549-54.</ref>
The result of the injury to these airway structures include extensive swelling of the the tongue, epiglottis, and aryepiglottic folds and accompanying obstruction. It takes a period of hours for airway swelling to develop as fluid resuscitation is taking place. It is important to note that initial evaluation might not be the best indicator of the extent of the obstruction that may later occur.<ref>Palmieri TL. Inhalation injury: research progress and needs. Journal of burn care & research. 2007 Jul 1;28(4):549-54.</ref>


=== Chemical Injury to the Lower Airways ===
=== Chemical Injury to the Lower Airways ===
Generation of materials toxic to the respiratory tract during burning may result in local chemical irritation throughout the respiratory tract.<ref name=":1" /> Burning rubber and plastic produces sulfur dioxide, nitrogen dioxide, ammonia and chlorine with strong acids and alkali when combined with water in the airways and alveoli. Laminated furniture contains glues and wall paneling also may release cyanide gas when burned. Burning cotton or wool produces toxic aldehydes. Smoke-related toxins damage epithelial and capillary endothelial cells of the airway.<ref name=":4" /><ref>Trunkey DD:Inhalation injury. Surg Clin North Am1978,58:1133–1140</ref>
Combustion of materials leads to the the production of toxic materials to the respiratory tract. This may cause local chemical irritation in the respiratory tract.<ref name=":1" /> Sulfur dioxide is produced by burning rubber and plastic, as well as other gases such as nitrogen dioxide, ammonia and chlorine with strong acids and alkali after combination with water in the respiratory airways and alveoli. Also, laminated furniture may contain glues that may release cyanide gas during combustion. Aldehydes are also produced when cotton or wool are burned. Furthermore, toxins produced by smoke may damage airway epithelial and capillary endothelial cells.<ref name=":4" /><ref>Trunkey DD:Inhalation injury. Surg Clin North Am1978,58:1133–1140</ref>


=== Systemic Toxicity due to Carbon Monoxide or Cyanide Exposure ===
=== Systemic Toxicity due to Carbon Monoxide or Cyanide Exposure ===
Carbon monoxide poisoning is a major source of early morbidity in burn-injured patients with many fatalities occurring at the scene of the fire due to this mechanism. Carboxyhemoglobin levels exceed 10% in a closed space fire. Significant injury may occur in a short period of time with the exposure with as little as 10% carboxyhemoglobin.<ref name=":4" /><ref>Moore SJ, Ho K, Hume AS. Severe hypoxia produced by concomitant intoxication with sublethal doses of carbon monoxide and cyanide. Toxicology and applied pharmacology. 1991 Jul 1;109(3):412-20.</ref><ref name=":5">Traber, D., Herndon, David, Enkhbaatar, Perenlei, Maybauer, Marc, Maybauer, Dirk. The pathophysiology of inhalation injury. In: Herndon, D., editor. Total Burn Care. Fourth. Saunders Elsevier; 2012. p. 219-28 </ref>Carbon monoxide competitively inhibits intracellular cytochrome oxidase enzyme systems, most notably cytochrome P-450 resulting in inability of cellular systems to utilize oxygen.<ref name=":1" />  
Fatalities result from carbon monoxide poisoning in burn-injured patients. Unfortunately, many of its fatalities happen at the scene of the fire due to its mechanism. In a closed fire space, the level of carboxyhemoglobin levels. This can result in significant injury in just a short time frame with the exposure to carboxyhemoglobin levels as minute as 10%.<ref name=":4" /><ref>Moore SJ, Ho K, Hume AS. Severe hypoxia produced by concomitant intoxication with sublethal doses of carbon monoxide and cyanide. Toxicology and applied pharmacology. 1991 Jul 1;109(3):412-20.</ref><ref name=":5">Traber, D., Herndon, David, Enkhbaatar, Perenlei, Maybauer, Marc, Maybauer, Dirk. The pathophysiology of inhalation injury. In: Herndon, D., editor. Total Burn Care. Fourth. Saunders Elsevier; 2012. p. 219-28 </ref> Carbon monoxide is a competitive inhibitor of intracellular cytochrome oxidase enzyme systems, especially the cytochrome P-450 resulting in inactivation of cellular systems to make use of oxygen.<ref name=":1" />  


Inhaled hydrogen cyanide, produced during combustion of multiple household materials, also inhibits the cytochrome oxidase system and may have a synergistic effect with carbon monoxide producing tissue hypoxia and acidosis as well as a decrease in cerebral oxygen consumption.<ref name=":4" /><ref name=":5" />  
On the other hand, inhaled hydrogen cyanide, which is a product of the combustion of multiple household materials also inhibits the cytochrome oxidase system. This then foster a synergy with carbon monoxide to cause tissue hypoxia with acidosis and a reduction in the consumption of oxygen by the brain tissues.<ref name=":4" /><ref name=":5" />  


== Pathophysiology ==
== Pathophysiology ==
The extent of damage from an inhalation injury depends on the environment and the host: the source of injury, temperature, concentration, and solubility of the toxic gases generated, and the response to that injury by the individual.<ref name=":6">Sousse LE, Herndon DN, Andersen CR, Ali A, Benjamin NC, Granchi T, Suman OE, Mlcak RP. High tidal volume decreases adult respiratory distress syndrome, atelectasis, and ventilator days compared with low tidal volume in pediatric burned patients with inhalation injury. Journal of the American College of Surgeons. 2015 Apr 1;220(4):570-8.</ref>  Inhalation injuries cause formation of casts, reduction of available surfactant, increased airway resistance, and decreased pulmonary compliance<ref name=":7">Jones, SW., Ortiz-Pujols, Shiara M., Cairns, Bruce. Smoke inhalation injury: a review of the pathophysiology, management, and challenges of burn-associated inhalation injury. In: Gilchrist ICaEYC. , editor. Current Concepts in Adult Critical Care Society of Critical Care Medicine. Vol. 2011. 2011.</ref> leading to acute lung injury and acute respiratory distress syndrome.<ref>Friedl HP, Till GO, Trentz O, Ward PA. Roles of histamine, complement and xanthine oxidase in thermal injury of skin. The American journal of pathology. 1989 Jul;135(1):203.</ref>  
What determines the amount of damage caused by an inhalation injury are the environment and the host. Also, other factors such as the injury source, the gases produced (temperature, concentration, and solubility), and the response of an individual to the injury.<ref name=":6">Sousse LE, Herndon DN, Andersen CR, Ali A, Benjamin NC, Granchi T, Suman OE, Mlcak RP. High tidal volume decreases adult respiratory distress syndrome, atelectasis, and ventilator days compared with low tidal volume in pediatric burned patients with inhalation injury. Journal of the American College of Surgeons. 2015 Apr 1;220(4):570-8.</ref>  The effects that follow inhalation injuries include formation of casts, reduction in the amount of available surfactants, increased airway resistance, and reduction in pulmonary compliance.<ref name=":7">Jones, SW., Ortiz-Pujols, Shiara M., Cairns, Bruce. Smoke inhalation injury: a review of the pathophysiology, management, and challenges of burn-associated inhalation injury. In: Gilchrist ICaEYC. , editor. Current Concepts in Adult Critical Care Society of Critical Care Medicine. Vol. 2011. 2011.</ref> These culminate in acute lung injury and acute respiratory distress syndrome.<ref>Friedl HP, Till GO, Trentz O, Ward PA. Roles of histamine, complement and xanthine oxidase in thermal injury of skin. The American journal of pathology. 1989 Jul;135(1):203.</ref>  


The mechanism of destruction can be classified in one of four ways:
This mechanism of destruction in inhalation injuries can be classified in one of four ways:


Upper Airway Injury
Upper Airway Injury


The major pathophysiology seen in the upper airway inhalation injury is induced by microvascular changes from direct thermal injury and chemical irritation.<ref name=":3" />The heat denatures protein, which subsequently activates the complement cascade causing the release of histamine.<ref name=":6" /><ref>Granger DN. Role of xanthine oxidase and granulocytes in ischemia-reperfusion injury. American Journal of Physiology-Heart and Circulatory Physiology. 1988 Dec 1;255(6):H1269-75.</ref> Subsequently, there is the formation of xanthine oxidase, and release of reactive oxygen species (ROS) which combines with nitric oxide in the endothelium to induce upper airway edema area by increasing the microvascular pressure and local permeability<ref name=":6" /><ref>Granger DN, Kvietys PR. Reperfusion injury and reactive oxygen species: the evolution of a concept. Redox biology. 2015 Dec 1;6:524-51.</ref><ref>Baile EM, Dahlby RW, Wiggs BR, Pare PD. Role of tracheal and bronchial circulation in respiratory heat exchange. Journal of Applied Physiology. 1985 Jan 1;58(1):217-22.</ref> Pro-inflammatory cytokines, ROS and Eicosanoids attract polymorphonuclear cells to the area further amplifying ROS and signaling proteases.<ref name=":0" />
The course of this pathophysiology is induced by microvascular changes that result after direct thermal injury and chemical irritation.<ref name=":3" /> Heat produced from the burn denatures protein. This causes the activation of the complement cascade that results in the release of histamine.<ref name=":6" /><ref>Granger DN. Role of xanthine oxidase and granulocytes in ischemia-reperfusion injury. American Journal of Physiology-Heart and Circulatory Physiology. 1988 Dec 1;255(6):H1269-75.</ref> Furthermore, xanthine oxidase is formed, reactive oxygen species (ROS) are released which reacts with nitric oxide in the endothelium to cause upper airway edema by raising the pressure of the microvasculature and local permeability.<ref name=":6" /><ref>Granger DN, Kvietys PR. Reperfusion injury and reactive oxygen species: the evolution of a concept. Redox biology. 2015 Dec 1;6:524-51.</ref><ref>Baile EM, Dahlby RW, Wiggs BR, Pare PD. Role of tracheal and bronchial circulation in respiratory heat exchange. Journal of Applied Physiology. 1985 Jan 1;58(1):217-22.</ref> Also, pro-inflammatory cytokines, with ROS and eicosanoids bring polymorphonuclear cells to this area further causing the release of ROS and signaling proteases.<ref name=":0" />


There is a substantial increase in microvascular hydrostatic pressure, a decrease in interstitial hydrostatic pressure and an increase in interstitial oncotic pressure.<ref name=":6" />  The hallmark of burn resuscitation is the administration of large amounts of crystalloid, which reduces plasma oncotic pressure affecting the oncotic pressure gradient in the microcirculation causing significantly more airway edema.<ref name=":6" /> Barring steam inhalation injuries and blast injuries, the upper airway efficiently protects the lower airway via heat exchange to limit distal damage to the lower airway.<ref name=":0" />
This causes a remarkable increase in the pressure of the microvasculature, a reduction in interstitial hydrostatic pressure and an increase in interstitial oncotic pressure.<ref name=":6" />  Since the mainstay of burn resuscitation is the administration of crystalloids in large amounts, this further reduces the plasma oncotic pressure, affecting the oncotic pressure gradient in the microcirculation causing more significant airway edema.<ref name=":6" /> Without steam inhalation and blast injuries, an efficient protection is given to the lower airway by the upper airway through heat exchange to restrict distal damage to the lower airways.<ref name=":0" />


Lower Airway Injury
Lower Airway Injury


Injury to the lower airway is due to the chemicals in smoke. The heat capacity of air is low and the bronchial circulation very efficient in warming or cooling the airway gases, so that most gases are at body temperature as they pass the glottis.<ref>Moritz AR, Henriques Jr FC, McLean R. The effects of inhaled heat on the air passages and lungs: an experimental investigation. The American journal of pathology. 1945 Mar;21(2):311.</ref> In order to induce thermal injury to the airway, flames must be in direct contact.<ref>Herndon DN, Barrow RE, Traber DL, Rutan TC, Rutan RL, Abston S. Extravascular lung water changes following smoke inhalation and massive burn injury. Surgery. 1987 Aug 1;102(2):341-9.</ref> Accelerants, or burned biological materials are caustic to the airways and induce an initial response to trigger proinflammatory response. There is a 10-fold increase in bronchial blood flow within minutes of an inhalation injury<ref name=":5" /> which is sustained and causes increased permeability and destruction of the bronchial epithelium.<ref name=":6" /> There is a subsequent increase in pulmonary transvascular fluid and a fall in PaO2/FiO2 ≤ 200 nearly 24 hours after injury.<ref>Walker PF, Buehner MF, Wood LA, Boyer NL, Driscoll IR, Lundy JB, Cancio LC, Chung KK. Diagnosis and management of inhalation injury: an updated review. Critical Care. 2015 Dec;19(1):1-2.</ref> There is a subsequent hyperemia of the tracheobronchial tree and lower airways and that clinical finding – so prevalent – is used to diagnose the injury.<ref name=":8">You K, Yang HT, Kym D, Yoon J, Cho YS, Hur J, Chun W, Kim JH. Inhalation injury in burn patients: establishing the link between diagnosis and prognosis. Burns. 2014 Dec 1;40(8):1470-5.</ref><ref>Pitt BR, Radford EP, Gurtner GH, Traystman RJ. Interaction of carbon monoxide and cyanide on cerebral circulation and metabolism. Archives of Environmental Health: An International Journal. 1979 Sep 1;34(5):354-9.</ref>Early in the injury, the secretions, from goblet cells, are copious and foamy in nature. In hours to days these secretions solidify forming casts and airway obstruction.<ref name=":6" />
Lower airway injury occurs as a result of the chemicals in smoke. Due to the low heat capacity of air and the efficient bronchial circulation regulating the temperature of the airway gases, most gases are at body temperature when the pass through the glottis.<ref>Moritz AR, Henriques Jr FC, McLean R. The effects of inhaled heat on the air passages and lungs: an experimental investigation. The American journal of pathology. 1945 Mar;21(2):311.</ref> For the induction of thermal injury to the airways, flames have to be in direct contact.<ref>Herndon DN, Barrow RE, Traber DL, Rutan TC, Rutan RL, Abston S. Extravascular lung water changes following smoke inhalation and massive burn injury. Surgery. 1987 Aug 1;102(2):341-9.</ref> Burned biological materials are toxic to the airways and cause an initial response to trigger proinflammatory response. This causes up to a 10-fold increase in bronchial blood circulation within minutes after an inhalation injury. <ref name=":5" /> This increase is sustained and results in increased permeability and damage of the bronchial epithelium.<ref name=":6" /> An increase in pulmonary transvascular fluid results and a fall in PaO2/FiO2 ≤ 200 within 24 hours following the injury.<ref>Walker PF, Buehner MF, Wood LA, Boyer NL, Driscoll IR, Lundy JB, Cancio LC, Chung KK. Diagnosis and management of inhalation injury: an updated review. Critical Care. 2015 Dec;19(1):1-2.</ref> Furthermore, hyperemia of the tracheobronchial tree and lower airways occurs, which is a clinical finding very common in inhalation injury and is used to often diagnose the injury.<ref name=":8">You K, Yang HT, Kym D, Yoon J, Cho YS, Hur J, Chun W, Kim JH. Inhalation injury in burn patients: establishing the link between diagnosis and prognosis. Burns. 2014 Dec 1;40(8):1470-5.</ref><ref>Pitt BR, Radford EP, Gurtner GH, Traystman RJ. Interaction of carbon monoxide and cyanide on cerebral circulation and metabolism. Archives of Environmental Health: An International Journal. 1979 Sep 1;34(5):354-9.</ref> The copious and foamy secretions that are formed from goblet cells later solidify, resulting in the formation of casts and airway obstruction.<ref name=":6" />


Pulmonary parenchymal injury
Pulmonary parenchymal injury


Changes to lung parenchyma are delayed, dependent on the severity of injury and the patient’s response to the injury. Parenchymal injuries are associated with an increase in pulmonary transvascular fluid which is directly proportional to the duration of exposure of smoke and toxins.<ref name=":1" /> As stated previously, injury to the lower airways and lung parenchyma is rarely due to direct thermal contact. Only steam can overcome the very efficient upper airway heat dissipating capabilities. There is a reduction to the permeability of protein, an increase in the permeability to small particles, an increase in pressure in the pulmonary microvasculature pressure, and a loss of hypoxic pulmonary vasoconstriction.<ref name=":6" /> The key pathological derangements in inhalation injury are edema, decreased pulmonary compliance from extravascular lung water and pulmonary lymph, and immediate inactivation of surfactant. There is a subsequent ventilation perfusion mismatch that can lead to profound hypoxemia and ARDS.<ref name=":3" />
The changes to lung parenchyma occur much later after the injury. The extent of this changes are dependent on the extent of the injury and the response of the patient to the injury. The occurrence of parenchymal injuries are associated with an elevation of pulmonary transvascular fluid levels and this is proportional to the period of exposure to toxins and smokes.<ref name=":1" /> Again, it is rare for injury to the lower airways and lung parenchyma to be caused by direct thermal contact. Thus, it is only steam that can overcome the efficient heat dissipating system of the upper airway. There is a decrease to the permeability of protein, an elevation to the permeability to small particles, a reduction in pressure in the pulmonary microvasculature pressure, and a loss of hypoxic pulmonary vasoconstriction.<ref name=":6" /> The major derangements that follow inhalation injury include edema, reduced pulmonary compliance from extravascular lung water and pulmonary lymph, and immediate inactivation of surfactant. In addition, a subsequent ventilation-perfusion mismatch can also occur that can lead to profound hypoxemia and ARDS.<ref name=":3" />


Systemic toxicity.
Systemic toxicity.


Systemic toxic changes are caused by the inhalation of chemicals and cytotoxic liquids, mists, fumes and gases. Smoke combines with these toxins and increases mortality by increasing tissue hypoxia, metabolic acidosis, and decreasing cerebral oxygen consumption and metabolism.<ref name=":5" /><ref>Moylan JA, Chan CK. Inhalation injury--an increasing problem. Annals of surgery. 1978 Jul;188(1):34.</ref>
Inhalation of chemicals, cytotoxic liquids, fumes, mist and gases can cause systemic toxic changes. Smoke can combine with these toxins and cause increased mortality by promoting tissue hypoxia, metabolic acidosis, and reducing cerebral oxygen consumption and metabolism.<ref name=":5" /><ref>Moylan JA, Chan CK. Inhalation injury--an increasing problem. Annals of surgery. 1978 Jul;188(1):34.</ref>


== Diagnosis ==
== Diagnosis ==

Revision as of 00:38, 8 December 2020

Original Editor - Joseph Ayotunde Aderonmu

Top Contributors - Joseph Ayotunde Aderonmu, Chelsea Mclene, Naomi O'Reilly and Kim Jackson  

Introduction[edit | edit source]

Respiratory System.png

Inhalation injury happens to be one of the most challenging injuries for burn care providers. This is because it is one of the classic determinants of mortality that occurs after severe burn injury. The other determinants are age, extent of injury, as well as delay in resuscitation.[1] Inhalation injury refers to pulmonary injury resulting from inhalation of smoke or chemical products of combustion.[2]

Inhalation injury causes localized damage by direct cellular damage, disruptions in regional blood flow and perfusion, obstruction of the airways, and toxin and pro-inflammatory cytokine release.[3][4] Inhalation injuries also causes reduced functionality of mucociliary clearance and weakening of alveolar macrophages.[5] With this, patient is placed at a high risk of bacterial infection, especially pneumonia, which is one of the top causes of death for burn patients.[6][7]

Epidemiology[edit | edit source]

Inhalation injury is recorded in about one-third of all burn injuries and it is responsible for about 90% of all burn-related mortality.[3][8] The National Burn Repository of the American Burn Association reported up to 10.3% of burn patients to have accompanying inhalation injury.[9] Thus, 1 in 10 burn patients that survive to admission will have the inhalation injury and a corresponding increase in the mortality rate.[10]

Classes[edit | edit source]

Anatomically, inhalation injuries are divided into three classes:[11]

Heat Injury to the Upper Airway[edit | edit source]

When the room air temperature reaches 1000°F after a fire outbreak, injury is results to structures of the airway above the carina. This results due to the combination of efficient heat dissipation in the upper airway, low heat capacity of air and reflex closure of the larynx.[12]

The result of the injury to these airway structures include extensive swelling of the the tongue, epiglottis, and aryepiglottic folds and accompanying obstruction. It takes a period of hours for airway swelling to develop as fluid resuscitation is taking place. It is important to note that initial evaluation might not be the best indicator of the extent of the obstruction that may later occur.[13]

Chemical Injury to the Lower Airways[edit | edit source]

Combustion of materials leads to the the production of toxic materials to the respiratory tract. This may cause local chemical irritation in the respiratory tract.[2] Sulfur dioxide is produced by burning rubber and plastic, as well as other gases such as nitrogen dioxide, ammonia and chlorine with strong acids and alkali after combination with water in the respiratory airways and alveoli. Also, laminated furniture may contain glues that may release cyanide gas during combustion. Aldehydes are also produced when cotton or wool are burned. Furthermore, toxins produced by smoke may damage airway epithelial and capillary endothelial cells.[11][14]

Systemic Toxicity due to Carbon Monoxide or Cyanide Exposure[edit | edit source]

Fatalities result from carbon monoxide poisoning in burn-injured patients. Unfortunately, many of its fatalities happen at the scene of the fire due to its mechanism. In a closed fire space, the level of carboxyhemoglobin levels. This can result in significant injury in just a short time frame with the exposure to carboxyhemoglobin levels as minute as 10%.[11][15][16] Carbon monoxide is a competitive inhibitor of intracellular cytochrome oxidase enzyme systems, especially the cytochrome P-450 resulting in inactivation of cellular systems to make use of oxygen.[2]

On the other hand, inhaled hydrogen cyanide, which is a product of the combustion of multiple household materials also inhibits the cytochrome oxidase system. This then foster a synergy with carbon monoxide to cause tissue hypoxia with acidosis and a reduction in the consumption of oxygen by the brain tissues.[11][16]

Pathophysiology[edit | edit source]

What determines the amount of damage caused by an inhalation injury are the environment and the host. Also, other factors such as the injury source, the gases produced (temperature, concentration, and solubility), and the response of an individual to the injury.[17] The effects that follow inhalation injuries include formation of casts, reduction in the amount of available surfactants, increased airway resistance, and reduction in pulmonary compliance.[18] These culminate in acute lung injury and acute respiratory distress syndrome.[19]

This mechanism of destruction in inhalation injuries can be classified in one of four ways:

Upper Airway Injury

The course of this pathophysiology is induced by microvascular changes that result after direct thermal injury and chemical irritation.[6] Heat produced from the burn denatures protein. This causes the activation of the complement cascade that results in the release of histamine.[17][20] Furthermore, xanthine oxidase is formed, reactive oxygen species (ROS) are released which reacts with nitric oxide in the endothelium to cause upper airway edema by raising the pressure of the microvasculature and local permeability.[17][21][22] Also, pro-inflammatory cytokines, with ROS and eicosanoids bring polymorphonuclear cells to this area further causing the release of ROS and signaling proteases.[1]

This causes a remarkable increase in the pressure of the microvasculature, a reduction in interstitial hydrostatic pressure and an increase in interstitial oncotic pressure.[17] Since the mainstay of burn resuscitation is the administration of crystalloids in large amounts, this further reduces the plasma oncotic pressure, affecting the oncotic pressure gradient in the microcirculation causing more significant airway edema.[17] Without steam inhalation and blast injuries, an efficient protection is given to the lower airway by the upper airway through heat exchange to restrict distal damage to the lower airways.[1]

Lower Airway Injury

Lower airway injury occurs as a result of the chemicals in smoke. Due to the low heat capacity of air and the efficient bronchial circulation regulating the temperature of the airway gases, most gases are at body temperature when the pass through the glottis.[23] For the induction of thermal injury to the airways, flames have to be in direct contact.[24] Burned biological materials are toxic to the airways and cause an initial response to trigger proinflammatory response. This causes up to a 10-fold increase in bronchial blood circulation within minutes after an inhalation injury. [16] This increase is sustained and results in increased permeability and damage of the bronchial epithelium.[17] An increase in pulmonary transvascular fluid results and a fall in PaO2/FiO2 ≤ 200 within 24 hours following the injury.[25] Furthermore, hyperemia of the tracheobronchial tree and lower airways occurs, which is a clinical finding very common in inhalation injury and is used to often diagnose the injury.[26][27] The copious and foamy secretions that are formed from goblet cells later solidify, resulting in the formation of casts and airway obstruction.[17]

Pulmonary parenchymal injury

The changes to lung parenchyma occur much later after the injury. The extent of this changes are dependent on the extent of the injury and the response of the patient to the injury. The occurrence of parenchymal injuries are associated with an elevation of pulmonary transvascular fluid levels and this is proportional to the period of exposure to toxins and smokes.[2] Again, it is rare for injury to the lower airways and lung parenchyma to be caused by direct thermal contact. Thus, it is only steam that can overcome the efficient heat dissipating system of the upper airway. There is a decrease to the permeability of protein, an elevation to the permeability to small particles, a reduction in pressure in the pulmonary microvasculature pressure, and a loss of hypoxic pulmonary vasoconstriction.[17] The major derangements that follow inhalation injury include edema, reduced pulmonary compliance from extravascular lung water and pulmonary lymph, and immediate inactivation of surfactant. In addition, a subsequent ventilation-perfusion mismatch can also occur that can lead to profound hypoxemia and ARDS.[6]

Systemic toxicity.

Inhalation of chemicals, cytotoxic liquids, fumes, mist and gases can cause systemic toxic changes. Smoke can combine with these toxins and cause increased mortality by promoting tissue hypoxia, metabolic acidosis, and reducing cerebral oxygen consumption and metabolism.[16][28]

Diagnosis[edit | edit source]

Traditionally, diagnosis of inhalation injury was based on the following indirect observations:[29]

  • Facial burns
  • Singed nasal vibrissae
  • A history of injury in an enclosed space

Taken individually, each of these signs has a high incidence of false positivity, but as a group they have been found to actually underestimate the true incidence of inhalation injury. Carbonaceous secretions represent another classic sign of smoke inhalation that is a less exact predictor of the presence or severity of injury than is popularly believed. Carbonaceous secretions should be regarded as an indicator of exposure to smoke but should not establish either the diagnosis of inhalation injury or its sequela. Hypoxia, rales, rhonchi and wheezes are seldom present on admission, occurring only in those with the most severe injury and implying an extremely poor prognosis.[6]

The admission chest X-ray has also been shown to be a very poor indicator.[6] Although two-thirds of patients develop changes of diffuse or focal infiltrates or pulmonary edema within 5–10 days of injury, the admission film is seldom diagnostic but is important for baseline evaluations.[30]

The current standard for diagnosis of inhalation injury in most major burn centers is fiberoptic bronchoscopy.[31] Useful only in identifying upper airway injury, findings include the presence of soot, charring, mucosal necrosis, airway edema and inflammation.[32]

Bronchoscopy without findings cannot rule out the possibility of parenchyma damage. To evaluate true parenchyma damage, Xenon scanning has been utilized.[33] This is a safe, rapid test requiring a minimum of patient cooperation, it involves serial chest scintiphotograms after an initial intravenous injection of radioactive Xenon gas. It demonstrates areas of the decreased alveolar gas washout, which identifies sites of small airway obstruction caused by edema or fibrin cast formation.[6]

Management[edit | edit source]

There is no consensus amongst leading burn centers the optimal treatment protocol for inhalation injury.[1] The fundamental tenet of treatment for inhalation injury is supportive care through the acute hospitalization and rehabilitation. [1]

Supportive Care[edit | edit source]

Inhalation injuries cause formation of casts, reduction of available surfactant, increased airway resistance, and decreased pulmonary compliance.[18] Patients require pulmonary toilet, physiotherapy, airway suctioning, therapeutic serial bronchoscopies, and early ambulation.[1]

Bronchodilators[edit | edit source]

Bronchodilators decrease airflow resistance and improve airway compliance. β2-adrenergic  agonists such as albuterol and salbutamol decrease airway pressure by relaxing smooth muscle and inhibiting bronchospasm thereby increasing the PaO2/FiO2 ratio.[34]

Muscarinic receptor antagonists[edit | edit source]

Muscarinic receptor antagonists such as tiotropium decrease airway pressures and mucus secretion and limit cytokine release by causing smooth muscle constriction within the airways, and stimulation of submucosal glands.[35][36]

Both beta agonists and muscarinic receptor antagonists decrease the host inflammatory response after inhalation injury. Anatomically, there are muscarinic and adrenergic receptors found lining the respiratory tract. How that impacts the inflammatory response and host response is largely unknown. They have been shown to decrease pro-inflammatory cytokines after stress.[37]

Inhaled (nebulized) Mucolytic agents and Anticoagulants[edit | edit source]

The airway obstruction secondary to mucus, fibrin cast formation, and cellular debris subsequent to inhalation injury are addressed by mucolytic agents, specifically, N Acetylcysteine (NAC).[38] NAC is an antioxidant and free radical scavenger with antiinflammatory properties.[39] It is a powerful mucolytic agent that attenuates ROS damage[26]. Inhaled anticoagulants are also used to mitigate airway obstruction from fibrin casts.

Respiratory support[edit | edit source]

There is often such significant upper airway edema from the inhalation injury, or the resuscitation of the cutaneous injury that leads to worsening airway edema. This physiologic consequence can be deadly and may progress expeditiously.[6] It is thus paramount to obtain and sustain a definitive airway early in treatment.[1]

There have been limited trials on the appropriate respiratory modes in patients with inhalation injury. A mechanical ventilation strategy shown to improve morbidity and mortality from ARDS and ALI comes from the ARDSNET trial, which showed in a large randomized controlled trial that lung protective strategies of limited tidal volumes of 6–8mL/kg and plateau pressures of less than 30cm H2O improved outcomes.[40]

Conventional mechanical ventilation modes, such as control mode ventilation, assist-control mode, synchronized intermittent mandatory ventilation, pressure control mode and pressure support mode are limited in the patient with inhalation injury.[18][41] Thus, in order to support these patients and apply lung-protective ventilation strategies in patients with inhalation injury, non-conventional ventilator modes are often employed.[42]

Popular among these non-conventional ventilator modes are high-frequency percussive ventilation (HFPV), high frequency oscillatory ventilation (HFOV), airway pressure release ventilation (APRV), extracorporeal membrane oxygenation (ECMO). HFPV has however shown the most promising results.[1]

Physiotherapy[edit | edit source]

Studies have shown that a combination of techniques such as gravity-assisted bronchial drainage with chest percussion and vibrations. are effective in secretion removal.[43][44][45]

Bronchial Drainage/Positioning[edit | edit source]

Bronchial drainage/positioning is a therapeutic modality which uses gravity-assisted positioning designed to improve pulmonary hygiene in patients with inhalation injury or retained secretions. Due to skin grafts, donor sites, and the use of air fluid beds, clinical judgment might influence the most appropriate decisions.[6] In fact, positioning in the Trendelenburg and various other positions may acutely worsen hypoxemia. Evidence has shown that a patient’s arterial oxygenation may fall during positioning.[45]

Percussion[edit | edit source]

It aids the removal of secretions from the tracheobronchial tree. There should be a padding between the patient and the percussor’s hand in order to prevent irritation of the skin.[6] Percussion is applied over the surface landmarks of the bronchial segments which are being drained. Incisions, skin grafts, and bony prominences should be avoided during percussion.[46]

Vibration/shaking[edit | edit source]

Vibration/shaking a shaking movement used to move loosened secretions to larger airways so that they can be coughed up or removed by suctioning. Vibration involves rapid shaking of the chest wall during exhalation. Mechanical vibrations have been reported to produce good clinical results. Gentle mechanical vibration may be indicated for patients who cannot tolerate manual percussion.[6]

Early Ambulation[edit | edit source]

Early ambulation is another effective means of preventing respiratory complications. With appropriate use of analgesics, even patients on continuous ventilatory support can be taken out of bed and placed into a chair. The sitting position has several beneficial effects which include:[6]

  • The patient can breathe with regions of the lungs which are normally hyperventilated
  • Muscular strength and tone are preserved
  • Contractions are prevented and exercise tolerance is maintained

Prognosis[edit | edit source]

While mortality rates for inhalation injury has not changed significantly over the last fifty years, the improvements in standards of care for severe burn injuries have.[1] Supportive strategies are vital in the management of inhalation injury, yet, large multi-centered trials are needed to demonstrate consistent results for many of the pharmacological adjuncts. HFPV as an unconventional mode of ventilation shows the most promising results and address the physiologic derangements from inhalation injury.[1]

Conclusion

Inhalation injury requires a robust knowledge of its pathophysiology to guide accurate diagnosis and drive the right therapeutic strategies. Practitioners must carefully work within available evidence for best outcomes from inhalation injuries –a classic determinant of mortality in severe burn.

References[edit | edit source]

  1. ↑ 1.0 1.1 1.2 1.3 1.4 1.5 1.6 1.7 1.8 1.9 Jones SW, Williams FN, Cairns BA, Cartotto R. Inhalation injury: pathophysiology, diagnosis, and treatment. Clinics in plastic surgery. 2017 Jul 1;44(3):505-11.
  2. ↑ 2.0 2.1 2.2 2.3 Dries and EndorfScandinavian Journal of Trauma, Resuscitation and Emergency Medicine2013,21:31
  3. ↑ 3.0 3.1 Kadri SS, Miller AC, Hohmann S, Bonne S, Nielsen C, Wells C, Gruver C, Quraishi SA, Sun J, Cai R, Morris PE. Risk factors for in-hospital mortality in smoke inhalation-associated acute lung injury: data from 68 United States hospitals. Chest. 2016 Dec 1;150(6):1260-8.
  4. ↑ 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. [PubMed: 24986596]
  5. ↑ Al Ashry HS, Mansour G, Kalil AC, Walters RW, Vivekanandan R. Incidence of ventilator associated pneumonia in burn patients with inhalation injury treated with high frequency percussive ventilation versus volume control ventilation: A systematic review. Burns. 2016 Sep 1;42(6):1193-200.
  6. ↑ 6.00 6.01 6.02 6.03 6.04 6.05 6.06 6.07 6.08 6.09 6.10 Mlcak RP, Suman OE, Herndon DN. Respiratory management of inhalation injury. burns. 2007 Feb 1;33(1):2-13.
  7. ↑ Pruitt BA, McManus AT. The changing epidemiology of infection in burn patients. World journal of surgery. 1992 Jan 1;16(1):57-67.
  8. ↑ Tan A, Smailes S, Friebel T, Magdum A, Frew Q, El-Muttardi N, Dziewulski P. Smoke inhalation increases intensive care requirements and morbidity in paediatric burns. Burns. 2016 Aug 1;42(5):1111-5.
  9. ↑ Burn Incidence Fact Sheet. American Burn Association; 2016 National Burn Repository. American Burn Association; 2017.
  10. ↑ Foncerrada G, Culnan DM, Capek KD, González-Trejo S, Cambiaso-Daniel J, Woodson LC, Herndon DN, Finnerty CC, Lee JO. Inhalation injury in the burned patient. Annals of plastic surgery. 2018 Mar;80(3 Suppl 2):S98.
  11. ↑ 11.0 11.1 11.2 11.3 McCall JE, Cahill TJ. Respiratory care of the burn patient. Journal of Burn Care & Rehabilitation. 2005 May 1;26(3):200-6.
  12. ↑ Pruitt Jr BA, Flemma RJ, DiVincenti FC, Foley FD, Mason Jr AD, Young Jr WG. Pulmonary complications in burn patients: a comparative study of 697 patients. The Journal of thoracic and cardiovascular surgery. 1970 Jan 1;59(1):7-20.
  13. ↑ Palmieri TL. Inhalation injury: research progress and needs. Journal of burn care & research. 2007 Jul 1;28(4):549-54.
  14. ↑ Trunkey DD:Inhalation injury. Surg Clin North Am1978,58:1133–1140
  15. ↑ Moore SJ, Ho K, Hume AS. Severe hypoxia produced by concomitant intoxication with sublethal doses of carbon monoxide and cyanide. Toxicology and applied pharmacology. 1991 Jul 1;109(3):412-20.
  16. ↑ 16.0 16.1 16.2 16.3 Traber, D., Herndon, David, Enkhbaatar, Perenlei, Maybauer, Marc, Maybauer, Dirk. The pathophysiology of inhalation injury. In: Herndon, D., editor. Total Burn Care. Fourth. Saunders Elsevier; 2012. p. 219-28 
  17. ↑ 17.0 17.1 17.2 17.3 17.4 17.5 17.6 17.7 Sousse LE, Herndon DN, Andersen CR, Ali A, Benjamin NC, Granchi T, Suman OE, Mlcak RP. High tidal volume decreases adult respiratory distress syndrome, atelectasis, and ventilator days compared with low tidal volume in pediatric burned patients with inhalation injury. Journal of the American College of Surgeons. 2015 Apr 1;220(4):570-8.
  18. ↑ 18.0 18.1 18.2 Jones, SW., Ortiz-Pujols, Shiara M., Cairns, Bruce. Smoke inhalation injury: a review of the pathophysiology, management, and challenges of burn-associated inhalation injury. In: Gilchrist ICaEYC. , editor. Current Concepts in Adult Critical Care Society of Critical Care Medicine. Vol. 2011. 2011.
  19. ↑ Friedl HP, Till GO, Trentz O, Ward PA. Roles of histamine, complement and xanthine oxidase in thermal injury of skin. The American journal of pathology. 1989 Jul;135(1):203.
  20. ↑ Granger DN. Role of xanthine oxidase and granulocytes in ischemia-reperfusion injury. American Journal of Physiology-Heart and Circulatory Physiology. 1988 Dec 1;255(6):H1269-75.
  21. ↑ Granger DN, Kvietys PR. Reperfusion injury and reactive oxygen species: the evolution of a concept. Redox biology. 2015 Dec 1;6:524-51.
  22. ↑ Baile EM, Dahlby RW, Wiggs BR, Pare PD. Role of tracheal and bronchial circulation in respiratory heat exchange. Journal of Applied Physiology. 1985 Jan 1;58(1):217-22.
  23. ↑ Moritz AR, Henriques Jr FC, McLean R. The effects of inhaled heat on the air passages and lungs: an experimental investigation. The American journal of pathology. 1945 Mar;21(2):311.
  24. ↑ Herndon DN, Barrow RE, Traber DL, Rutan TC, Rutan RL, Abston S. Extravascular lung water changes following smoke inhalation and massive burn injury. Surgery. 1987 Aug 1;102(2):341-9.
  25. ↑ Walker PF, Buehner MF, Wood LA, Boyer NL, Driscoll IR, Lundy JB, Cancio LC, Chung KK. Diagnosis and management of inhalation injury: an updated review. Critical Care. 2015 Dec;19(1):1-2.
  26. ↑ 26.0 26.1 You K, Yang HT, Kym D, Yoon J, Cho YS, Hur J, Chun W, Kim JH. Inhalation injury in burn patients: establishing the link between diagnosis and prognosis. Burns. 2014 Dec 1;40(8):1470-5.
  27. ↑ Pitt BR, Radford EP, Gurtner GH, Traystman RJ. Interaction of carbon monoxide and cyanide on cerebral circulation and metabolism. Archives of Environmental Health: An International Journal. 1979 Sep 1;34(5):354-9.
  28. ↑ Moylan JA, Chan CK. Inhalation injury--an increasing problem. Annals of surgery. 1978 Jul;188(1):34.
  29. ↑ Putman CE, Loke JA, Matthay RA, Ravin CE. Radiographic manifestations of acute smoke inhalation. American Journal of Roentgenology. 1977 Nov 1;129(5):865-70.
  30. ↑ Wanner A, Cutchavaree A. Early recognition of upper airway obstruction following smoke inhalation. American Review of Respiratory Disease. 1973 Dec;108(6):1421-3.
  31. ↑ Moylan JA, Adib K, Birnbaum M. Fiberoptic bronchoscopy following thermal injury. Plastic and Reconstructive Surgery. 1975 Nov 1;56(5):598.
  32. ↑ Moylan Jr JA, Wilmore DW, Mouton DE, Pruitt Jr BA. Early diagnosis of inhalation injury using 133 xenon lung scan. Annals of surgery. 1972 Oct;176(4):477.
  33. ↑ Lange M, Hamahata A, Traber DL, Cox RA, Kulp GA, Nakano Y, Traber LD, Herndon DN, Enkhbaatar P. Preclinical evaluation of epinephrine nebulization to reduce airway hyperemia and improve oxygenation after smoke inhalation injury. Critical care medicine. 2011 Apr;39(4).
  34. ↑ Dries DJ, Endorf FW. Inhalation injury: epidemiology, pathology, treatment strategies. Scandinavian journal of trauma, resuscitation and emergency medicine. 2013 Dec 1;21(1):31.
  35. ↑ Jonkam C, Zhu Y, Jacob S, Rehberg S, Kraft E, Hamahata A, Nakano Y, Traber LD, Herndon DN, Traber DL, Hawkins HK. Muscarinic receptor antagonist therapy improves acute pulmonary dysfunction after smoke inhalation injury in sheep. Critical care medicine. 2010 Dec 1;38(12):2339-44.
  36. ↑ 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. The Journal of clinical investigation. 1996 Feb 1;97(3):713-9.
  37. ↑ Suter PM, Domenighetti G, Schaller MD, Laverrière MC, Ritz R, Perret C. N-acetylcysteine enhances recovery from acute lung injury in man: a randomized, double-blind, placebo-controlled clinical study. Chest. 1994 Jan 1;105(1):190-4.
  38. ↑ Villegas L, Stidham T, Nozik-Grayck E. Oxidative stress and therapeutic development in lung diseases. Journal of pulmonary & respiratory medicine. 2014 Aug;4(4).
  39. ↑ Acute Respiratory Distress Syndrome Network. Ventilation with lower tidal volumes as compared with traditional tidal volumes for acute lung injury and the acute respiratory distress syndrome. New England Journal of Medicine. 2000 May 4;342(18):1301-8.
  40. ↑ Petrucci N, Iacovelli W. Lung protective ventilation strategy for the acute respiratory distress syndrome. Cochrane Database of Systematic Reviews. 2007(3).
  41. ↑ Fitzpatrick JC, Cioffi Jr WG. Ventilatory support following burns and smoke-inhalation injury. Respiratory care clinics of North America. 1997 Mar 1;3(1):21-49.
  42. ↑ Chopra SK, Taplin GV, Simmons DH, Robinson Jr GD, Elam D, Coulson A. Effects of hydration and physical therapy on tracheal transport velocity. American Review of Respiratory Disease. 1977 Jun;115(6):1009-14.
  43. ↑ Marini JJ, Pierson DJ, Hudson LD. Acute lobar atelectasis: a prospective comparison of fiberoptic bronchoscopy and respiratory therapy. American Review of Respiratory Disease. 1979 Jun;119(6):971-8.
  44. ↑ Oldenburg Jr FA, Dolovich MB, Montgomery JM, Newhouse MT. Effects of postural drainage, exercise, and cough on mucus clearance in chronic bronchitis. American Review of Respiratory Disease. 1979 Oct;120(4):739-45.
  45. ↑ 45.0 45.1 Remolina C, Khan AU, Santiago TV, Edelman NH. Positional Hypoxemia in Unilateral Lung Disease. Survey of Anesthesiology. 1982 Feb 1;26(1):1.
  46. ↑ Herndon DN, Inhalation injury. In: Total burn care; 2nd ed., 2002, p. 242–53.
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