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1. Name of Chemical Defense therapeutic agent/device

Surfactant

2. Chemical Defense therapeutic area(s)

— including key possible uses

Surfactant can be used to treat chemically-induced acute lung injury by phosgene, sulfur mustard, nerve agent VX

3. Evidence-based medicine for Chemical Defense

— including efficacy and safety

A. Summary

Mechanism of action

Endogenous pulmonary surfactant (a complex mixture of phospholipids, proteins, and neutral lipids) reduces surface tension at the air-liquid interface of the alveoli during ventilation and stabilizes the alveoli against collapse at resting transpulmonary pressures.
Exogenous surfactants compensate for deficiency of endogenous surfactant and restore surface activity to the lungs of infants.

In vitro, CUROSURF lowers minimum surface tension to ≤4mN/m as measured by the Wilhelmy Balance System.
In vivo, in several pharmacodynamic studies, CUROSURF improved lung compliance, pulmonary gas exchange, or survival in premature rabbits.

Product Label: CUROSURF (poractant alfa) suspension
[Chiesi USA, Inc] Last revised: June 2012 [DailyMed]

Infasurf adsorbs rapidly to the surface of the air:liquid interface and modifies surface tension similarly to natural lung surfactant. A minimum surface tension of less than or equal to 3 mN/m is produced in vitro by Infasurf as measured on a pulsating bubble surfactometer. Ex vivo, Infasurf restores the pressure volume mechanics and compliance of surfactant-deficient rat lungs.
In vivo, Infasurf improves lung compliance, respiratory gas exchange, and survival in preterm lambs with profound surfactant deficiency.

Product Label: INFASURF (calfactant) suspension
[Ony, Inc.] Last revised: July 2011 [DailyMed]

In vitro, SURVANTA reproducibly lowers minimum surface tension to less than 8 dynes/cm as measured by the pulsating bubble surfactometer and Wilhelmy Surface Balance. In situ, SURVANTA restores pulmonary compliance to excised rat lungs artificially made surfactant-deficient.
In vivo, single SURVANTA doses improve lung pressure-volume measurements, lung compliance, and oxygenation in premature rabbits and sheep.

Product Label: SURVANTA (beractant) suspension
[AbbVie Inc.] Last revised: February 2012 [DailyMed]

Summary of clinical and non-clinical studies

Pulmonary surfactant is a complex mixture of proteins, phospholipids, and neutral lipids produced by alveoli to serve two major functions: it lowers surface tension, reducing airway resistance and facilitating adequate ventilation of the lung, and it enhances the lungs' defense mechanisms against bacteria and viruses (Turell, 2008). In animal models, chemical weapons including phosgene and sulfur mustard destroy and/or alter the composition of lung surfactant (Jugg et al., 1999; van Helden et al., 2004; Pauluhn et al., 2007), suggesting that intratracheal application of exogenous natural or synthetic surfactants can restore lung function after exposure to such agents. Surfactants have been used to treat human patients suffering from acute lung injury (ALI) or the most severe form of ALI, acute respiratory distress syndrome (ARDS), to mixed success. In a randomized trial of exogenous calfactant (a modified natural bovine surfactant) versus placebo in children with ALI, the calfactant group showed a significant improvement in oxygenation (p=0.01) after 12 hours, and a significant reduction in mortality compared with the placebo group (15/77 versus 27/75; odds ratio, 2.32; 95% confidence interval, 1.15-4.85), although there were no differences in ventilator-free days and long-term complications (Willson et al., 2005). A case study of a 19 month old girl treated for ARDS (secondary to aspiration of lamp oil) reported that her oxygenation improved markedly after one dose of calfactant administered 10 hours after ingestion (Mastropietro and Valentine, 2011). After a second dose at 19 hours, she was progressively weaned from artificial ventilation and extubated with no residual lung disease. On the other hand, two recent international, multicenter, randomized trials in adult ALI/ARDS patients using the natural porcine surfactant HL-10 (Kesecioglu et al., 2009) or recombinant surface protein C (rSP-C) (Spragg et al., 2011) showed no significant improvement in mortality or blood oxygenation. ARDS can have diverse causes, and an earlier meta-analysis of rSP-C clinical trials suggested that subgroups of patients who experienced ARDS as a result of direct lung injury were more likely to see improved oxygenation (though not improved mortality) from exogenous surfactant than patients with ARDS secondary to vascular or interstitial disease processes (Taut et al., 2008).

Studies in animal models suggest that exogenous surfactant is a potentially useful therapy in response to chemical weapons. In guinea pigs exposed to the nerve agent VX at a concentration resulting in a 52% 24-hour survival rate, treatment with surfactant alone after 2 minutes did not improve survival rate (1/4 animals survived), though the nasally-administered anticholinergic agent atropine methyl nitrate (AMN) resulted in a 100% survival rate (6/6) (Nambiar et al., 2007). However, AMN in conjunction with surfactant reduced the signs of lung damage, including the amount of free protein, cells, and dead cells found in bronchoalveolar lavage (BAL), to a greater extent than AMN alone, suggesting that surfactant can be a useful adjunct to atropine for restoring lung function. Guinea pigs exposed to the median lethal dose (LD₅₀) of sulfur mustard showed evidence that endogenous surfactant was altered; intratracheal administration of Curosurf, a natural surfactant, 1 hour after intoxication resulted in 24-hour survival rates of 83% (at 62.5 mg/kg Curosurf) and 67% (at 125 mg/kg Curosurf) compared to 50% of control animals, though survival rates for both dosing groups dropped to 50% at 72 and 96 hours, the same as the control animals at the same time points (van Helden et al., 2004). Differences between control and treatment groups were not statistically significant (p>0.05), but this could be considered a preliminary signal of efficacy, perhaps as an adjunct to other therapies. Exogenous surfactants have also demonstrated efficacy against lung injury by aspirated hydrochloric acid: after acid inhalation, Surfacten (a bovine extract) reduced the edema and partially restored oxygenation in rats (Jian et al., 2010), and aerosolized phospholipid nanovesicles improved airway patency and reduced alveolar protein leakage in mice (Kaviratna and Banerjee, 2012).

B. Link to clinical studies

Studies involving multiple populations

BACKGROUND: Studies to date have shown no survival benefit for the use of exogenous surfactant to treat patients with the ARDS. To identify specific patient subgroups for future study, an exploratory post hoc analysis of clinical trials of recombinant surfactant protein-C (rSP-C) surfactant (Venticute; Nycomed GmbH; Konstanz, Germany) was performed. METHODS: A pooled analysis was performed of all five multicenter studies in which patients with ARDS due to various predisposing events were treated with rSP-C surfactant. Patients received either usual care (n = 266) or usual care plus up to four intratracheal doses (50 mg/kg) of rSP-C surfactant (n = 266). Factors influencing the study end points were analyzed using descriptive statistics, analysis of covariance, and logistic regression models. RESULTS: ARDS was most often associated with pneumonia or aspiration, sepsis, and trauma or surgery. For the overall patient population, treatment with rSP-C surfactant significantly improved oxygenation (p = 0.002) but had no effect on mortality (32.6%). Multivariate analysis showed age and acute physiology and chronic health evaluation (APACHE) II score to be the strongest predictors of mortality. In the subgroup of patients with severe ARDS due to pneumonia or aspiration, surfactant treatment was associated with markedly improved oxygenation (p = 0.0008) and improved survival (p = 0.018). CONCLUSIONS: rSP-C surfactant improved oxygenation in patients with ARDS irrespective of the predisposition. Post hoc evidence of reduced mortality associated with surfactant treatment was obtained in patients with severe respiratory insufficiency due to pneumonia or aspiration. Those patients are the focus of a current randomized, blinded, clinical trial with rSP-C surfactant. (Class III)

Taut FJH, Rippin G, Schenk P, et al; A Search for subgroups of patients with ARDS who may benefit from surfactant replacement therapy: a pooled analysis of five studies with recombinant surfactant protein-C surfactant (Venticute). Chest, 2008 Oct;134(4):724-32. [PubMed Citation]

Adult

RATIONALE: Compositional changes in surfactant and/or decreased surfactant content of the lungs are common features in patients with acute respiratory failure. Instillation of exogenous surfactant into the lungs of neonates with respiratory distress syndrome or pediatric patients with acute respiratory distress syndrome (ARDS) has resulted in improved survival. OBJECTIVES: This trial was conducted to determine whether the instillation of exogenous surfactant would improve the Day 28 outcome of adult patients with acute lung injury (ALI) or ARDS. METHODS: A total of 418 patients with ALI and ARDS were included in an international, multicenter, stratified, randomized, controlled, open, parallel-group study. 418 patients were randomly assigned to receive usual care either with or without instillation of exogenous natural porcine surfactant HL 10 as large boluses. MEASUREMENTS AND MAIN RESULTS: The primary endpoint was death rate before or on Day 28. Secondary endpoints were adverse event and death rate on day 180. The 28-day death rate in the usual care group was 24.5% compared with 28.8% in the HL 10 group. The estimated odds ratio for death at Day 28 in the usual care group versus the HL 10 group was 0.75 (95% CI, 0.48-1.18; P = 0.22). The most common adverse events related to HL 10 administration were temporary hypoxemia defined as oxygen saturation less than 88% (51.9% in HL 10 group vs. 25.2% in usual care) and hypotension defined as mean arterial blood pressure less than 60 mm Hg (34.1% in HL 10 group vs. 17.1% in usual care). CONCLUSIONS: In this study, instillation of a large bolus of exogenous natural porcine surfactant HL 10 into patients with acute lung injury and ARDS did not improve outcome and showed a trend toward increased mortality and adverse effects. Clinical trial registered with www.clinicaltrials.gov (NCT 00742482). (Class II)

Kesecioglu J, Beale R, Stewart TE, George P. Findlay GP, Jean-Jacques Rouby J-J, Holzapfel L, Bruins P, Steenken EJ, Jeppesen OK, and Lachmann B. Exogenous Natural Surfactant for Treatment of Acute Lung Injury and the Acute Respiratory Distress Syndrome. Am J Respir Crit Care Med. 2009 Nov; 180(10):989-994 [PubMed Citation]

Rationale: Patients with acute lung injury have impaired function of the lung surfactant system. Prior clinical trials have shown that treatment with exogenous recombinant surfactant protein C (rSP-C)- based surfactant results in improvement in blood oxygenation and have suggested that treatment of patients with severe direct lung injury may decrease mortality. Objectives: Determine the clinical benefit of administering an rSP-C- based synthetic surfactant to patients with severe direct lung injury due to pneumonia or aspiration. Methods: A prospective randomized blinded study was performed at 161 centers in 22 countries. Patients were randomly allocated to receive usual care plus up to eight doses of rSP-C surfactant administered over 96 hours (n = 419) or only usual care (n = 424). Measurements and Main Results: Mortality to 28 days after treatment, the requirement for mechanical ventilation, and the number of nonpulmonary organ failure-free days were not different between study groups. In contrast to prior studies, there was no improvement in oxygenation in patients receiving surfactant compared with the usual care group. Investigation of the possible reasons underlying the lack of efficacy suggested a partial inactivation of rSP-C surfactant caused by a step of the resuspension process that was introduced with this study. Conclusions: In this study, rSP-C-based surfactant was of no clinical benefit to patients with severe direct lung injury. The unexpected lack of improvement in oxygenation, coupled with the results of in vitro tests, suggest that the administered suspension may have had insufficient surface activity to achieve clinical benefit. (Class II)

Spragg RG, Taut JH, Lewis JF, Schenk P, Ruppert C, Dean N, Krell K, Karabinis A, and Gunther A. Recombinant Surfactant Protein C-based Surfactant for Patients with Severe Direct Lung Injury. Am J Respir Crit Care Med. 2011 Apr;183(8):1055-1061 [PubMed Citation]

Pediatric studies

CONTEXT: Despite evidence that patients with acute lung injury (ALI) have pulmonary surfactant dysfunction, trials of several surfactant preparations to treat adults with ALI have not been successful. Preliminary studies in children with ALI have shown that instillation of a natural lung surfactant (calfactant) containing high levels of surfactant-specific protein B may be beneficial. OBJECTIVE: To determine if endotracheal instillation of calfactant in infants, children, and adolescents with ALI would shorten the course of respiratory failure. DESIGN, SETTING, AND PATIENTS: A multicenter, randomized, blinded trial of calfactant compared with placebo in 153 infants, children, and adolescents with respiratory failure from ALI conducted from July 2000 to July 2003. Twenty-one tertiary care pediatric intensive care units participated. Entry criteria included age 1 week to 21 years, enrollment within 48 hours of endotracheal intubation, radiological evidence of bilateral lung disease, and an oxygenation index higher than 7. Premature infants and children with preexisting lung, cardiac, or central nervous system disease were excluded. INTERVENTION: Treatment with intratracheal instillation of 2 doses of 80 mL/m2 calfactant or an equal volume of air placebo administered 12 hours apart. MAIN OUTCOME MEASURES: Ventilator-free days and mortality; secondary outcome measures were hospital course, adverse events, and failure of conventional mechanical ventilation. RESULTS: The calfactant group experienced an acute mean (SD) decrease in oxygenation index from 20 (12.9) to 13.9 (9.6) after 12 hours compared with the placebo group's decrease from 20.5 (14.7) to 15.1 (9.0) (P = .01). Mortality was significantly greater in the placebo group compared with the calfactant group (27/75 vs 15/77; odds ratio, 2.32; 95% confidence interval, 1.15-4.85), although ventilator-free days were not different. More patients in the placebo group did not respond to conventional mechanical ventilation. There were no differences in long-term complications. CONCLUSIONS: Calfactant acutely improved oxygenation and significantly decreased mortality in infants, children, and adolescents with ALI although no significant decrease in the course of respiratory failure measured by duration of ventilator therapy, intensive care unit, or hospital stay was observed. (Class II)

Willson DF, Thomas NJ, Markovitz BP, et al; Effect of exogenous surfactant (calfactant) in pediatric acute lung injury: a randomized controlled trial. JAMA, 2005 Jan 26; 293(4):470-6. [PubMed Citation]

Hydrocarbon ingestions account for a substantial number of accidental poisonings; when aspirated, it can lead to severe pneumonitis. Treatment for severe pneumonitis is generally supportive, and outcomes are frequently poor. The authors report here the case of a 19-month-old girl who was treated successfully with early administration of exogenous surfactant for acute respiratory distress syndrome secondary to aspiration of lamp oil. Approximately 7 hours after aspiration, she required mechanical ventilation and had an oxygenation index (OI) of 13.2. Approximately 10 hours after ingestion, exogenous surfactant (calfactant) was instilled intratracheally, after which her OI improved markedly to 4.3. She received a second dose about 19 hours after ingestion, after which her OI remained at <5 and she was progressively weaned from mechanical ventilation. She was extubated 64 hours after the ingestion with no residual lung disease. This case illustrates the importance of considering exogenous surfactant therapy early in the course of acute respiratory failure secondary to hydrocarbon aspiration. Because of the putative mechanisms of lung injury involved in hydrocarbon aspiration, surfactant-replacement therapy is a reasonable therapeutic intervention based on pathophysiologic rationale. (Class IV)

Mastropietro CW, Valentine K. Early administration of intratracheal surfactant (calfactant) after hydrocarbon aspiration. Pediatrics. 2011 Jun; 127(6):e1600-4. [PubMed Citation]

Clinical reviews

Surfactant is a biologic agent found in the lungs that reduces surface tension, allowing for adequate respiration. This compound was discovered in the early twentieth century. Its use has had a dramatic impact in the field of neonatology, namely in the treatment of Respiratory Distress Syndrome (RDS) and Meconium Aspiration Syndrome (MAS). These pulmonary conditions are caused by a primary surfactant deficiency and surfactant inactivation, respectively. Recent research has focused on secondary surfactant deficiency as a result of lung injury from a variety of medical conditions. In this article, the physiology of surfactant is reviewed along with the research that lead to its current clinical uses. Acute lung injury (ALI) and Acute Respiratory Distress Syndrome (ARDS) will also be reviewed because they represent a pulmonary disease process in which secondary deficiency and surfactant inactivation occur, and for which surfactant may prove to be an effective treatment. Finally, research using surfactant as a treatment for other pulmonary diseases, such as bronchiolitis and asthma, will be briefly highlighted. These studies may one day lead to new treatment opportunities in the realm of emergency medicine. (Class IV)

Turell DC. Advances with Surfactant. Emerg Med Clin N Am. 2008 Nov;26(4):921-928 [PubMed Citation]

This article reviews exogenous surfactant therapy and its use in mitigating acute lung injury (ALI) and the acute respiratory distress syndrome (ARDS) in infants, children, and adults. Biophysical and animal research documenting surfactant dysfunction in ALI/ARDS is described, and the scientific rationale for treatment with exogenous surfactant is discussed. Major emphasis is placed on reviewing clinical studies of surfactant therapy in pediatric and adult patients who have ALI/ARDS. Particular advantages from surfactant therapy in direct pulmonary forms of these syndromes are described. Also discussed are additional factors affecting the efficacy of exogenous surfactants in ALI/ARDS (Class IV).

Willson DF, Chess PR, Notter RH. Surfactant for pediatric acute lung injury. Pediatr Clin N Am 2008;55:545-575 [PubMed Citation]

Supportive advances have been made to improve the care of patients with the Acute Respiratory Distress Syndrome (ARDS) but no pharmacologic interventions are known to reduce the high mortality of this disorder once it is established. This commentary discusses some of the challenges that arise in preventing ARDS in at-risk individuals and the likely dependence of this approach on biomarker panels that can be done in real time (Class IV).

Repine JJ, Crader KM, Elkins ND, Wilson P, Repine JE. Preventing the Acute Respiratory Distress Syndrome. Prev Med. 2012 May;54:S17-S19 [PubMed Citation]

Significant morbidity and mortality from smoke inhalation occurs in victims of fire. Lung injury can be caused by chemical and thermal insults. A variety of noxious gases, irritants and asphyxiants are generated depending on the material burnt. Carbon monoxide is the predominant cause of death among fire victims. Treatment should be directed at reversing hypoxemia as a result of asphyxia or carbon monoxide poisoning. There is no evidence that the routine use of corticosteroids or prophylactic antibiotics is beneficial. Through a better understanding of the pathophysiology of smoke-induced lung injury, the effects of exogenous surfactant, leukotriene inhibitors, antioxidants, nitric oxide synthase inhibitors and fibrinolytics suggest that these compounds may have a future therapeutic role in smoke-induced injury. Studies are needed to evaluate the safety and efficacy of these potential therapies before they are used clinically (Class IV).

Lee AS and Mellins RB. Lung injury from smoke inhalation. Paediatric Respiratory Reviews 2006;7:123-128 [PubMed Citation]

Acute respiratory distress syndrome (ARDS) is a life threatening respiratory failure due to lung injury from a variety of precipitants. Pathologically ARDS is characterised by diffuse alveolar damage, alveolar capillary leakage, and protein rich pulmonary edema leading to the clinical manifestation of poor lung compliance, severe hypoxemia, and bilateral infiltrates on chest radiograph. Several etiological factors associated with the development of ARDS are identified with sepsis, pneumonia, and trauma with multiple transfusions accounting for most cases. Despite the absence of a robust diagnostic definition, extensive epidemiological investigations suggest ARDS remains a significant health burden with substantial morbidity and mortality. Improvements in outcome following ARDS over the past decade are in part due to improved strategies of mechanical ventilation and advanced support of other failing organs. Optimal treatment involves judicious fluid management, protective lung ventilation with low tidal volumes and moderate positive end expiratory pressure, multi-organ support, and treatment where possible of the underlying cause. Moreover, advances in general supportive measures such as appropriate antimicrobial therapy, early enteral nutrition, prophylaxis against venous thromboembolism and gastrointestinal ulceration are likely contributory reasons for the improved outcomes. Although therapies such as corticosteroids, nitric oxide, prostacyclins, exogenous surfactants, ketoconazole and antioxidants have shown promising clinical effects in animal models, these have failed to translate positively in human studies. Most recently, clinical trials with β2 agonists aiding alveolar fluid clearance and immunonutrition with omega-3 fatty acids have also provided disappointing results. Despite these negative studies, mortality seems to be in decline due to advances in overall patient care. Future directions of research are likely to concentrate on identifying potential biomarkers or genetic markers to facilitate diagnosis, with phenotyping of patients to predict outcome and treatment response. Pharmacotherapies remain experimental and recent advances in the modulation of inflammation and novel cellular based therapies, such as mesenchymal stem cells, may reduce lung injury and facilitate repair (Class IV).

Dushianthan A, Grocott MPW, Postle AD, Cusak R. Acute respiratory distress syndrome and acute lung injury. Postgrad Med J. 2011 Sep;87(1031):612-22. [PubMed Citation]

PURPOSE OF REVIEW: Studies of the pharmacologic management of acute respiratory distress syndrome (ARDS) have yielded conflicting results. The purpose of this review is to discuss recent pharmacologic trials in ARDS, using the conceptual framework of ARDS as a heterogeneous disease. RECENT FINDINGS: Whereas most drug trials in ARDS have been negative, some studies suggest that targeting therapies at subgroups of patients may be successful. Proposed subgroups include early versus late-phase ARDS, direct versus indirect lung injury, and patients with altered coagulation. Corticosteroids have beneficial short-term effects when given at low or moderate doses sooner than 2 weeks but appear to be harmful if initiated later and are of unclear benefit if lung protective ventilation is also used. Surfactant may be helpful in patients with direct lung injury. Anticoagulants and vasodilators may have a greater chance for success in the subset of patients with vascular disease and a high dead-space fraction may identify such a population. SUMMARY: ARDS is a heterogeneous syndrome. Failure to target subgroups more likely to benefit from specific therapies may be one explanation for largely disappointing trial results so far (Class IV).

Frank AJ, Thompson BT. Pharmacological treatments for acute respiratory distress syndrome. Curr Opin Crit Care. 2010 Feb; 16(1):62-8. [PubMed Citation]

C. Link to non-clinical (e.g., animal) studies

Adult animal studies

The purpose of the present study was to investigate: (1) the acute effects of sulfur mustard on airway, lung, and surface tension of bronchoalveolar lavage fluid (BALfluid) in guinea pigs following intratracheal (i.t.) exposure to 1LD50 of an aerosolized solution of sulfur mustard in saline, and (2) the therapeutic efficacy of i.t. administration of the natural surfactant Curosurf and the broncholytic Salbutamol. Intratracheally aerosolized sulfur mustard solution induced two clinically relevant symptoms, that is, asthmalike symptoms reflected by an early bronchoconstriction and "late asthmatic responses" (LAR), and ARDS-like symptoms, that is, pulmonary edema and damage to the lung surfactant. The respiratory minute volume (RMV) was enhanced. Histologically, inflammation and severe epithelial injury in the upper airways were observed, whereas the lungs were homogeneously affected. The surface tension of BAL fluid derived at 24 h after sulfur mustard exposure was much higher (20 +/- 1 mN/m) than that of unexposed control animals (about 1.0 +/- 0.5 mN/m), indicating that the lung surfactant had been altered, and justifying treatment with exogenous surfactant. Intratracheal nebulization of a Salbutamol solution (10 microg/kg), or i.t. bolus administration of Curosurf (62.5 or 125 mg/kg), tended to reduce mortality, although Salbutamol appeared to be more effective than Curosurf in this respect. Although the present study does not give a definite answer to the question of whether the animal model used would be the most relevant for humans, a number of considerations in favor of i.t. aerosolization of sulfur mustard are discussed. Since it was noticed that sulfur mustard exposure induced damage to the lung surfactant, severe bronchoconstriction, and inflammation of the respiratory tract, the effectiveness of a combined treatment consisting of exogenous surfactant, anti-inflammatory drugs, and broncholytics is recommended to be further investigated.

van Helden HPM, Kuijpers WC, Diemel RV; Asthmalike Symptoms Following Intratracheal Exposure. Inhal Toxicol, 2004 Jul; 16(8):537-48. [PubMed Citation]

Acute lung injury causes inactivation of pulmonary surfactant due to leakage of albumin and other markers. Current surfactants are ineffective in this condition and are instilled intratracheally. Nanovesicles of 300 ± 50 nm composed of nonlamellar phospholipids were developed as pulmonary surfactant aerosols for therapy in acid-induced lung injury. A combination of dipalmitoyl phosphatidylcholine and dioleoyl phosphatidylethanolamine was used. The size and composition of the nanovesicles were optimized for an improved airway patency in the presence of albumin and serum. In an acid-induced lung injury model in mice, on treatment with nanovesicle aerosols at a dose of 200 mg/kg, the alveolar protein leakage decreased from 8.62 ± 0.97 μg/mL to 1.94 ± 0.74 μg/mL, whereas the airway patency of the bronchoalveolar lavage fluid increased from 0.6 ± 0.0% to 91.7 ± 1.05%. Nanovesicle aerosols of nonlamellar lipids improved the resistance of pulmonary surfactants to inhibition and were promising as a noninvasive aerosol therapy in acute lung injury.

Kaviratna AS, Banerjee R. Nanovesicle aerosols as surfactant therapy in lung injury. Nanomedicine: Nanotechnology, Biology, and Medicine 2012 Jul;8(5):665-672 [PubMed Citation]

To develop therapeutics against lung injury and respiratory toxicity following nerve agent VX exposure, we evaluated the protective efficacy of a number of potential pulmonary therapeutics. Guinea pigs were exposed to 27.03 mg/m3 of VX or saline using a microinstillation inhalation exposure technique for 4 min and then the toxicity was assessed. Exposure to this dose of VX resulted in a 24-h survival rate of 52%. There was a significant increase in bronchoalveolar lavage (BAL) protein, total cell number, and cell death. Surprisingly, direct pulmonary treatment with surfactant, liquivent, N-acetylcysteine, dexamethasone, or anti-sense syk oligonucleotides 2 min post-exposure did not significantly increase the survival rate of VX-exposed guinea pigs. Further blocking the nostrils, airway, and bronchioles, VX-induced viscous mucous secretions were exacerbated by these aerosolized treatments. To overcome these events, the authors developed a strategy to protect the animals by treatment with atropine. Atropine inhibits muscarinic stimulation and markedly reduces the copious airway secretion following nerve agent exposure. Indeed, post exposure treatment with atropine methyl bromide, which does not cross the blood-brain barrier, resulted in 100% survival of VX-exposed animals. Bronchoalveolar lavage from VX-exposed and atropine-treated animals exhibited lower protein levels, cell number, and cell death compared to VX-exposed controls, indicating less lung injury. When pulmonary therapeutics were combined with atropine, significant protection to VX-exposure was observed. These results indicate that combinations of pulmonary therapeutics with atropine or drugs that inhibit mucous secretion are important for the treatment of respiratory toxicity and lung injury following VX exposure.

Nambiar MP, Gordon RK, Rezk PE, Katos AM, Wajda NA, Moran TS, Steele KE, Doctor BP, Sciuto AM. Medical countermeasure against respiratory toxicity and acute lung injury following inhalation exposure to chemical warfare nerve agent VX.Toxicology and Applied Pharmacology 2007 Mar;219(2-3):142-150 [PubMed Citation]

This study investigated whether the reactive organohalogen gases perfluoroisobutene (PFIB) and phosgene, which cause death by overwhelming pulmonary edema, affect the surfactant system or type II pneumocytes of rat lung. The progression and type of pulmonary injury in Porton Wistar-derived rats was monitored over a 48 h period following exposure to either PFIB or phosgene (LCt30) by analyzing the inflammatory cells and protein in bronchoalveolar lavage fluid. Six rat lung phospholipids were measured by high-performance liquid chromatography, following solid phase extraction from lavage fluid. Alterations in the cell population and lung permeability occurred following both gases, indicating that the injury was a permeability-type pulmonary edema. Changes in the total amount of phospholipid and in the percentage composition of the surfactant were different for the two gases. PFIB produced increases in phosphatidylglycerol and phosphatidylcholine over the first hour, similar to that seen following air exposure, followed by substantial decreases in these phospholipids. Phosgene caused late increases in all phospholipids from 6 h post-exposure. Differences in the response of the surfactant system to exposure to PFIB and phosgene suggest different mechanisms of action at the alveolar surface although the final injurious response is pulmonary edema for both gases.

Jugg B, Jenner J, Rice P. The effect of perfluoroisobutene and phosgene on rat lavage fluid surfactant phospholipids. Human & Experimental Toxicology 1999 Nov; 18(11):659-668 [PubMed Citation]

The efficacy of exogenous surfactant administration is influenced by numerous factors, which has resulted in variable outcomes of clinical trials evaluating this treatment for the acute respiratory distress syndrome (ARDS). Several of these factors were investigated in an animal model of acid aspiration including different surfactant preparations, and different delivery methods. In addition, high-frequency oscillation (HFO), a mode of mechanical ventilation known to recruit severely damaged lungs, was utilized. Lung injury was induced in adult rabbits via intratracheal instillation of 0.2 N HCl followed by conventional mechanical ventilation (CMV) until PaO2/FIO2 values ranged from 220 to 270 mm Hg. Subsequently, animals were given one of three surfactants administered via three different methods and physiological responses were assessed over a 1-h period. Regardless of the surfactant treatment strategy utilized, oxygenation responses were not sustained. In contrast, HFO resulted in a superior response compared with all surfactant treatment strategies involving CMV. The deterioration in physiological parameters after surfactant treatment was likely due to overwhelming protein inhibition of the surfactant. In conclusion, various surfactant treatment strategies were not effective in this model of lung injury, although the lungs of these animals were recruitable with HFO, as reflected by the acute and sustained oxygenation improvements.

Brackenbury AM, Puligandla PS, McCaig LA, Nikore V, Yao L-J, Veldhuizen RAW, and Lewis JF. Evaluation of Exogenous Surfactant in HCl-induced Lung Injury. Am J Respir Crit Care Med 2001 Apr;163(5):1135-1142 [PubMed Citation]

The purpose of this study was to evaluate early vs. late administration of exogenous surfactant in an adult rabbit model of acute lung injury. Lung injury was induced by repetitive whole lung saline lavage and subsequent mechanical ventilation. Bovine lipid extract surfactant was instilled either 1 (Early) or 4 h (Late) after the last lavage. Animals were monitored for 7 h after the last lavage. Although arterial PO2 values increased significantly immediately after treatment in both the Early and Late groups, this improvement was not sustained in the Late group. There was also a higher incidence of pneumothoraxes in the Late group vs. both the Early group and a nontreated control group. The ratio of poorly functioning small surfactant aggregates to superior functioning large aggregates was higher in the Late group compared with the Early group. Morphological analysis revealed that early surfactant treatment prevented the progression of lung injury over time. The authors conclude that administration of exogenous surfactant at an early time point in lung injury resulted in superior responses compared with later treatments.

Ito Y, Goffin J, Veldhuizen R, Joseph M, Bjarneson D, McCaig L, Yao LJ, Marcou J, Lewis J. Timing of exogenous surfactant administration in a rabbit model of acute lung injury. J Appl Physiol. 1996 Apr; 80(4):1357-64 [PubMed Citation]

Pulmonary surfactant replacement has previously been shown to be effective in the human neonatal respiratory distress syndrome. The value of surfactant replacement in models of acute lung injury other than quantitative surfactant deficiency states is, however, uncertain. In this study an acute lung injury model using rats with chronic indwelling arterial catheters, injured with N-nitroso-N-methylurethane (NNNMU), has been developed. The NNNMU injury was found to produce hypoxia, increased mortality, an alveolitis, and alterations in the pulmonary surfactant system. Alterations of surfactant obtained by bronchoalveolar lavage included a reduction in the phospholipid-to-protein ratio, reduced surface activity, and alterations in the relative percentages of the individual phospholipids compared with controls. Treatment of the NNNMU-injured rats with instilled exogenous surfactant (Survanta) improved oxygenation; reduced mortality to control values; and returned the surfactant phospholipid-to-protein ratio, surface activity, and, with the exception of phosphatidylglycerol, the relative percentages of individual surfactant phospholipids to control values.

Harris JD, Jackson F Jr, Moxley MA, Longmore WJ. Effect of exogenous surfactant instillation on experimental acute lung injury. J Appl Physiol. 1989 Apr; 66(4):1846-51 [PubMed Citation]

Juvenile animal studies

The present study was performed to investigate the role of exogenous surfactant on hydrochloric acid (HCl) - induced lung injury in rats. Six-week-old male Sprague-Dawley rats were anesthetized by intraperitoneal injection of pentobarbital sodium (40 mg/kg) and HCl (0.1 N, 2 mL/kg) or normal saline (NS, 2 mL/kg) was instilled into the trachea. Thirty minutes after HCl instillation, surfactant at a dose of 60 mg (equals 2 mL)/body or NS (2 mL) was instilled into the rat lungs. Animals in another experimental group were also treated with the same dose of surfactant supplement 2 hours after the first administration. Bronchoalveolar lavage fluid (BALF) was obtained 5 hours after HCl instillation. In BALF, increases in total nuclear cell counts, neutrophil counts, optical density at 412 nm as an indicator of pulmonary hemorrhage, neutrophil elastase activity, concentrations of albumin and cytokine-induced neutrophil chemo attractant (CINC) induced by HCl instillation were significantly attenuated by surfactant treatment. The wet-to-dry weight (W/D) ratio in the lung and partial oxygen tension (PO2) were also estimated; surfactant treatment significantly attenuated the W/D ratio and improved deteriorated PO2 induced by HCl. Additional surfactant supplementation did not show further beneficial effects on HCl-induced lung injury compared with a single treatment. These results suggest that surfactant shows an anti-inflammatory effect on acid lung injury in rats but the beneficial effects may be dose limited.

Jian M-Y, Koizumi T, Tsushima K, Yokoyama T, Kubo K, Baba A. Exogenous surfactant instillation attenuates inflammatory response to acid-induced lung injury in rat. Pulmonary Pharmacology & Therapeutics 2010 Feb;23(1):43-47 [PubMed Citation]

Objectives: To test the hypothesis that surfactant, when given prophylactically during one lung ventilation (OLV), improves physiological stability and reduces inflammation. Methods: Prospective controlled animal study. After 30 min of mechanical ventilation, surfactant was administered to the left lung of the treatment group. Right lung mechanical ventilation continued for 3 hr, after which the left lung was unblocked. Bilateral mechanical ventilation was continued for 30 min thereafter. Physiological parameters and biomarkers of inflammation in plasma, lung tissue homogenates, and bronchoalveolar lavage (BAL) were measured. Measurements and Main Results: Oxygenation improved in the surfactant group, reaching statistical significance at 3 hr of OLV and again after 30 min of bilateral mechanical ventilation following the OLV. Plasma levels of interleukin (IL)-1 b, IL6, and tumor necrosis factor (TNF)-a showed a trend for reduction. The lung homogenates from the ventilated lungs had significantly lower levels of IL-1 b (P < 0.01) and IL-6 (P < 0.01). The BAL specimen showed an overall reduction in the cytokine levels; IL-1 b was significantly lower in the ventilated lungs (P < 0.01). Conclusions: Surfactant administration improves oxygenation and decreases inflammation, as evidenced by a decrease in several inflammatory cytokines both in the plasma and lungs of a piglet model of OLV.

Bhatia R, Shaffer TH, Hossain J, Fisher AO, Horner LM, Rodriguez ME, Penfil S, and Theroux MC. Surfactant Administration Prior to One Lung Ventilation: Physiological and Inflammatory Correlates in a Piglet Model. Pediatr Pulmonol. 2011 Nov;46(11):1069-1078 [PubMed Citation]

Non-clinical reviews

Sulfur mustard (SM) is highly toxic to the lung inducing both acute and chronic effects including upper and lower obstructive disease, airway inflammation, and acute respiratory distress syndrome, and with time, tracheobronchial stenosis, bronchitis, and bronchiolitis obliterans. Thus it is essential to identify effective strategies to mitigate the toxicity of SM and related vesicants. Studies in animals and in cell culture models have identified key mechanistic pathways mediating their toxicity, which may be relevant targets for the development of countermeasures. For example, following SM poisoning, DNA damage, apoptosis, and autophagy are observed in the lung, along with increased expression of activated caspases and DNA repair enzymes, biochemical markers of these activities. This is associated with inflammatory cell accumulation in the respiratory tract and increased expression of tumor necrosis factor-a and other proinflammatory cytokines, as well as reactive oxygen and nitrogen species. Matrix metalloproteinases are also upregulated in the lung after SM exposure, which are thought to contribute to the detachment of epithelial cells from basement membranes and disruption of the pulmonary epithelial barrier. Findings that production of inflammatory mediators correlates directly with altered lung function suggests that they play a key role in toxicity. In this regard, specific therapeutic interventions currently under investigation include anti-inflammatory agents (e.g., steroids), antioxidants (e.g., tocopherols, melatonin, N-acetylcysteine, nitric oxide synthase inhibitors), protease inhibitors (e.g., doxycycline, aprotinin, ilomastat), surfactant replacement, and bronchodilators. Effective treatments may depend on the extent of lung injury and require a multi-faceted pharmacological approach.

Weinberger B, Laskin JD, Sunil VR, Patrick J. Sinko PJ, Heck DE, Debra L. Laskin DL. Sulfur mustard-induced pulmonary injury: Therapeutic approaches to mitigating Toxicity. Pulm Pharmacol Ther. 2011 Feb; 24(1):92-9 [PubMed Citation].

A workshop was held February 14, 2007, in Arlington, VA, under the auspices of the Phosgene Panel of the American Chemistry Council. The objective of this workshop was to convene inhalation toxicologists and medical experts from academia, industry and regulatory authorities to critically discuss past and recent inhalation studies of phosgene in controlled animal models. This included presentations addressing the benefits and limitations of rodent (mice, rats) and nonrodent (dogs) species to study concentration x time (C x t) relationships of acute and chronic types of pulmonary changes. Toxicological endpoints focused on the primary pulmonary effects associated with the acute inhalation exposure to phosgene gas and responses secondary to injury. A consensus was reached that the phosgene-induced increased pulmonary extravasation of fluid and protein can suitably be probed by bronchoalveolar lavage (BAL) techniques. BAL fluid analyses rank among the most sensitive methods to detect phosgene-induced noncardiogenic, pulmonary high-permeability edema following acute inhalation exposure. Maximum protein concentrations in BAL fluid occurred within 1 day after exposure, typically followed by a latency period up to about 15 h, which is reciprocal to the C x t exposure relationship. The C x t relationship was constant over a wide range of concentrations and single exposure durations. Following intermittent, repeated exposures of fixed duration, increased tolerance to recurrent exposures occurred. For such exposure regimens, chronic effects appear to be clearly dependent on the concentration rather than the cumulative concentration x time relationship. The threshold C x t product based on an increased BAL fluid protein following single exposure was essentially identical to the respective C x t product following subchronic exposure of rats based on increased pulmonary collagen and influx of inflammatory cells. Thus, the chronic outcome appears to be contingent upon the acute pulmonary threshold dose. Exposure concentrations high enough to elicit an increased acute extravasation of plasma constituents into the alveolus may also be associated with surfactant dysfunction, intra-alveolar accumulation of fibrin and collagen, and increased recruitment and activation of inflammatory cells. Although the exact mechanisms of toxicity have not yet been completely elucidated, consensus was reached that the acute pulmonary toxicity of phosgene gas is consistent with a simple, irritant mode of action at the site of its initial deposition/retention. The acute concentration x time mortality relationship of phosgene gas in rats is extremely steep, which is typical for a local, directly acting pulmonary irritant gas. Due to the high lipophilicity of phosgene gas, it efficiently penetrates the lower respiratory tract. Indeed, more recent published evidence from animals or humans has not revealed appreciable irritant responses in central and upper airways, unless exposure was to almost lethal concentrations. The comparison of acute inhalation studies in rats and dogs with focus on changes in BAL fluid constituents demonstrates that dogs are approximately three to four times less susceptible to phosgene than rats under methodologically similar conditions. There are data to suggest that the dog may be useful particularly for the study of mechanisms associated with the acute extravasation of plasma constituents because of its size and general morphology and physiology of the lung as well as its oronasal breathing patterns. However, the study of the long-term sequelae of acute effects is experimentally markedly more demanding in dogs as compared to rats, precluding the dog model to be applied on a routine base. The striking similarity of threshold concentrations from single exposure (increased protein in BAL fluid) and repeated-exposure 3-mo inhalation studies (increased pulmonary collagen deposition) in rats supports the notion that chronic changes depend on acute threshold mechanisms.

Pauluhn J, Carson A, Costa DL, Gordon T, Kodavanti U, Last JA, Matthay MA, Pinkerton KE, Scuito AM. Workshop summary: phosgene-induced pulmonary toxicity revisited: appraisal of early and late markers of pulmonary injury from animal models with emphasis on human significance. Inhal Toxicol.2007 Aug; 19(10):789-810.

Surfactant - Medical Countermeasures Database

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