Electric Cell-Substrate Impedance Sensing (ECIS) as a Platform for Evaluating Barrier-Function Susceptibility and Damage from Pulmonary Atelectrauma.

Biophysical insults that either reduce barrier function (COVID-19, smoke inhalation, aspiration, and inflammation) or increase mechanical stress (surfactant dysfunction) make the lung more susceptible to atelectrauma. We investigate the susceptibility and time-dependent disruption of barrier function associated with pulmonary atelectrauma of epithelial cells that occurs in acute respiratory distress syndrome (ARDS) and ventilator-induced lung injury (VILI). This in vitro study was performed using Electric Cell-substrate Impedance Sensing (ECIS) as a noninvasive evaluating technique for repetitive stress stimulus/response on monolayers of the human lung epithelial cell line NCI-H441. Atelectrauma was mimicked through recruitment/derecruitment (RD) of a semi-infinite air bubble to the fluid-occluded micro-channel. We show that a confluent monolayer with a high level of barrier function is nearly impervious to atelectrauma for hundreds of RD events. Nevertheless, barrier function is eventually diminished, and after a critical number of RD insults, the monolayer disintegrates exponentially. Confluent layers with lower initial barrier function are less resilient. These results indicate that the first line of defense from atelectrauma resides with intercellular binding. After disruption, the epithelial layer community protection is diminished and atelectrauma ensues. ECIS may provide a platform for identifying damaging stimuli, ventilation scenarios, or pharmaceuticals that can reduce susceptibility or enhance barrier-function recovery.

Association of low FVC spirometric pattern with WTC occupational exposures.

BACKGROUND: A reduced forced vital capacity without obstruction (low FVC) is the predominant spirometric abnormality reported in workers and volunteers exposed to dust, gases, and fumes at the World Trade Center (WTC) disaster site in 2001-2002. While low FVC has been associated with obesity and metabolic syndrome, its association with WTC occupational exposures has not been demonstrated. We estimated the prevalence of this abnormality and examined its association with WTC exposure level. METHODS: Longitudinal study of the relation between arrival at the WTC site within 48 h and FVC below the lower limit of normal (FVC < LLN, with normal FEV1/FVC ratio) at any time in 10,284 workers with at least two spirometries between 2002 and 2018. Logistic regression and linear mixed models were used for the multivariable analyses. RESULTS: The prevalence of low FVC increased from 17.0% (95% CI 15.4%, 18.5%) in June 2003, to 26.4% (95% CI 24.8%, 28.1%) in June 2018, and exceeded at both times that of obstruction. The rate of FVC decline was -43.7 ml/year during the study period. In a multivariable analysis adjusting for obesity, metabolic syndrome indicators, and other factors, early arrival at the WTC disaster site was significantly associated with low FVC, but only among men (ORadj = 1.29, 95% CI 1.17, 1.43). Longitudinal FVC rate of decline did not differ by WTC site arrival time. CONCLUSIONS: Among WTC workers, the prevalence of low FVC increased over a 16-year period. Early arrival to the WTC disaster site was significantly associated with low FVC in males.

Cutaneous burn diminishes beneficial effect of intravenously administered mesenchymal stem cells on acute lung injury induced by smoke inhalation in sheep.

OBJECTIVE: To investigate effects of intravenously administered allogeneic mesenchymal stem cells (MSCs) on burn/smoke-induced lung injury. METHODS: Sheep were subjected to 40%, third-degree flame skin burn and smoke inhalation under deep anesthesia and analgesia. One-hour after injury, PlasmaLite A (control) or 200 million MSCs (treatment) were intravenously administered. Pulmonary oxygenation index, PaO2/FiO2 ratio, lung-lymph flow, and bloodless lung wet-to-dry weight ratio were measured. Distribution of MSCs and stromal cell-derived factor-1 (Sdf-1) protein level were determined in lung and skin tissues. Effects of burn exudate on MSCs migration were characterized. RESULTS: MSCs did not attenuate pulmonary dysfunction. The number of MSCs was significantly higher in lungs of sheep with smoke inhalation compared with those with burn/smoke injury. In contrast, number of MSCs was significantly higher beneath burned skin in sheep with burn/smoke than in unburned skin of sheep with smoke inhalation only. Expression of Sdf-1 protein was increased in the burned skin compared to unburned skin. Effects of burn exudate on cultured MSCs proliferation differed depending on collection time. CONCLUSION: Skin burn diminishes beneficial effects of MSCs on smoke-induced lung injury, by promoting migration of MSCs from the pulmonary tissue to the injured skin area, possibly via expression of Sdf-1 protein.

Chronic cigarette smoke exposure triggers a vicious cycle of leukocyte and endothelial-mediated oxidant stress that results in vascular dysfunction.

Although there is a strong association between cigarette smoking exposure (CSE) and vascular endothelial dysfunction (VED), the underlying mechanisms by which CSE triggers VED remain unclear. Therefore, studies were performed to define these mechanisms using a chronic mouse model of cigarette smoking (CS)-induced cardiovascular disease mirroring that in humans. C57BL/6 male mice were subjected to CSE for up to 48 wk. CSE impaired acetylcholine (ACh)-induced relaxation of aortic and mesenteric segments and triggered hypertension, with mean arterial blood pressure at 32 and 48 wk of exposure of 122 ± 6 and 135 ± 5 mmHg compared with 99 ± 4 and 102 ± 6 mmHg, respectively, in air-exposed mice. CSE led to monocyte activation with superoxide generation in blood exiting the pulmonary circulation. Macrophage infiltration with concomitant increase in NADPH oxidase subunits p22phox and gp91phox was seen in aortas of CS-exposed mice at 16 wk, with further increase out to 48 wk. Associated with this, increased superoxide production was detected that decreased with Nox inhibition. Tetrahydrobiopterin was progressively depleted in CS-exposed mice but not in air-exposed controls, resulting in endothelial nitric oxide synthase (eNOS) uncoupling and secondary superoxide generation. CSE led to a time-dependent decrease in eNOS and Akt expression and phosphorylation. Overall, CSE induces vascular monocyte infiltration with increased NADPH oxidase-mediated reactive oxygen species generation and depletes the eNOS cofactor tetrahydrobiopterin, uncoupling eNOS and triggering a vicious cycle of oxidative stress with VED and hypertension. Our study provides important insights toward understanding the process by which smoking contributes to the genesis of cardiovascular disease and identifies biomarkers predictive of disease.NEW & NOTEWORTHY In a chronic model of smoking-induced cardiovascular disease, we define underlying mechanisms of smoking-induced vascular endothelial dysfunction (VED). Smoking exposure triggered VED and hypertension and led to vascular macrophage infiltration with concomitant increase in superoxide and NADPH oxidase levels as early as 16 wk of exposure. This oxidative stress was accompanied by tetrahydrobiopterin depletion, resulting in endothelial nitric oxide synthase uncoupling with further superoxide generation triggering a vicious cycle of oxidative stress and VED.

Blood carboxyhemoglobin elimination curve, half-lifetime, and arterial-venous differences in acute phase of carbon monoxide poisoning in ovine smoke inhalation injury model.

Smoke inhalation injury (SII) affects more than 50,000 people annually causing carbon monoxide (CO) poisoning. Although the increased blood level of carboxyhemoglobin (CO-Hb) is frequently used to confirm the diagnosis of SII, knowledge of its elimination in the acute phase is still limited. The aim of this study is to determine CO-Hb elimination rates and their differences in arterial (aCO-Hb) and mixed-venous (vCO-Hb) blood following severe SII in a clinically relevant ovine model. Forty-three chronically instrumented female sheep were subjected to SII (12 breaths, 4 sets) through tracheostomy tube under anesthesia and analgesia. After the SII, sheep were awakened and placed on a mechanical ventilator (FiO2 = 1.0, tidal volume 12 mL/kg, and PEEP = 5cmH2O) and monitored. Arterial and mixed-venous blood samples were withdrawn simultaneously for blood gas analysis at various time points to determine CO-HB half-lifetime and an elimination curve. The mean of highest aCO-Hb level during SII was 70.8 ± 13.9%. The aCO-Hb elimination curve showed an approximated exponential decay during the first 60 min. Per mixed linear regression model analysis, aCO-Hb significantly (p < 0.001) declined (4.3%/minute) with a decay constant lambda of 0.044. With this lambda, mean lifetime and half-lifetime of aCO-Hb were 22.7 and 15.7 min, respectively. The aCO-Hb was significantly lower compared to vCO-Hb at all-time points (0-180 min). To our knowledge, this is the first report describing CO-Hb elimination curve in the acute phase after severe SII in the clinically relevant ovine model. Our data shows that CO-Hb is decreasing in linear manner with supportive mechanical ventilation (0-60 min). The results may help to understand CO-Hb elimination curve in the acute phase and improvement of pre-hospital and initial clinical care in patients with CO poisoning.

Inhalational injury and the larynx: A review.

OBJECTIVE: To review and discuss the existing research on the pathophysiology, impact and management of inhalational injury on the larynx and lower respiratory tract. DATA SOURCES: A literature search was conducted on the PubMed, MedLine, Embase, Web of Science and Google Scholar databases based on the keywords "airway burn", "inhalational injury" and "larynx". REVIEW METHODS: Inclusion criteria included English language studies containing original and review data on airway injury. Data was reported using the Preferred Reporting Items for Systematic Reviews and Meta-Analysis guidelines. CONCLUSIONS: Abnormal laryngeal and lower airway findings are common in burns patients and the incidence tends to increase with severity of the burns. Most patients with abnormal findings remain dysphonic decades after the initial injury. Larynx, the inlet to the airway, is exposed to the most intense thermal damage and highest concentration of chemical in inhalational injury. Airway injury is common and may result in long term morbidity. Healing of this tissue architecture is prolonged and different from cutaneous burn. Many patients receive prolonged intubation for medical complications that arise due to the burn injury. The degree of subglottic damage, however, is more extensive and occurs sooner compared with those without inhalational injuries. IMPLICATIONS FOR PRACTICE: With advances in acute medical and surgical management of burn and inhalational injury, airway injury is an important secondary outcome with lasting impact. Awareness of these potential complications and early involvement of medical and allied health team are important steps in improving patient care. A multi-disciplinary approach to management will optimise the short and long-term morbidity management and ultimately our patients' quality of life.

Prevalence of Tuberculosis Risk Factors among Bacteriologically Negative and Bacteriologically Confirmed Tuberculosis Patients from Five Regional Referral Hospitals in Uganda.

Understanding risk factors for tuberculosis (TB) and their prevalence helps guide early diagnosis. We determined their prevalence among bacteriologically negative and bacteriologically confirmed TB patients in five regional referral hospitals in Uganda. This cross-sectional study considered 1,862 adult presumptive TB participants. We performed fluorescent microscopy, Xpert MTB/RIF (Xpert), Lowenstein-Jensen culture, human immunodeficiency virus, and random blood sugar testing on recruited patients. Prevalence and prevalence ratios of risk factors were compared among bacteriologically negative and confirmed cases. Odds ratios and 95% confidence interval (CI) were determined for significant risk factors in bacteriologically confirmed patients. Of the 1,862 participants, 978 (55%) were male and the median age of the participants was 36 years (interquartile range: 27-48). Up to 273 (15%) had a positive result on all three TB tests. Most prevalent risk factors (prevalence ratio [PR] > 1.0) among bacteriologically negative and positive TB patients were cigarette smoking (9.3% versus 2.1%; PR = 2.1), biosmoke (24% versus 39.7%; PR = 1.7), contact (4.2% versus 6.5%; PR = 1.6), male gender (51.4% versus 72.5%; PR = 1.4), alcohol use (17.2% versus 24.4%; PR = 1.4), diabetes (0.7% versus 0.9%; PR = 1.3), and family history of TB (12.1% versus 13.7%; PR = 1.1). The risk factors and their adjusted prevalence rate ratios (95% CI) of being bacteriologically positive were male (1.8 [1.4-2.4]), biosmoke exposure (1.5 [1.2-2.0]), and history of cigarette smoking (1.6 [1.1-2.4]). Among bacteriologically confirmed patients in Uganda, cigarette smoking, biosmoke exposure, contact, male gender, alcohol use, diabetes, and family history of TB are important risk factors for TB. Interventions for TB control in people with these risk factors would help in TB control efforts.

Emergency department management of smoke inhalation injury in adults.

Smoke inhalation injury portends increased morbidity and mortality in fire-exposed patients. Upper airway thermal burns, inflammation from lower airway irritants, and systemic effects of carbon monoxide and cyanide can contribute to injury. A standardized diagnostic protocol for inhalation injury is lacking, and management remains mostly supportive. Clinicians should maintain a high index of suspicion for concomitant traumatic injuries. Diagnosis is mostly clinical, aided by bronchoscopy and other supplementary tests. Treatment includes airway and respiratory support, lung protective ventilation, 100% oxygen or hyperbaric oxygen therapy for carbon monoxide poisoning, and hydroxocobalamin for cyanide toxicity. Due to its progressive nature, many patients with smoke inhalation injury warrant close monitoring for development of airway compromise.

The differential expression of novel circular RNAs in an acute lung injury rat model caused by smoke inhalation.

Acute lung injury caused by smoke inhalation is a common severe clinical syndrome. This study aimed to investigate the potential expression of circular RNAs during acute lung injury triggered by smoke inhalation. The acute lung injury rat model was established with smoke inhalation from a self-made smoke generator. The occurrence of acute lung injury was validated by an analysis of the bronchoalveolar lavage fluid and hematoxylin-eosin (HE) staining of lung tissues. Next-generation sequencing and quantitative PCR were performed to identify the differentially expressed circular RNAs associated with acute lung injury that was caused by smoke inhalation. The circular form of the identified RNAs was finally verified by multiple RT-PCR-based assays. The bronchoalveolar lavage fluid (BALF) and lung tissue analysis showed that smoke inhalation successfully induced acute injury in rats, as evidenced by the significantly altered cell numbers, including macrophages, neutrophils, and red blood cells, disrupted cell lining, and increased levels of interleukin-1ß, tumor necrosis factor-alpha, and IL-8 in lung tissues. Ten significantly differentially expressed circular RNAs were identified with next-generation sequencing and RT-PCR. The circular form of these RNAs was verified by multiple RT-PCR-based assays. In conclusion, the identified circular RNAs were prevalently and differentially expressed in rat lungs after acute lung injury caused by smoke inhalation.

R-100 improves pulmonary function and systemic fluid balance in sheep with combined smoke-inhalation injury and Pseudomonas aeruginosa sepsis.

BACKGROUND: Septic shock is a major cause of death in intensive care units around the world . The aim of the study was to investigate whether the novel drug R-100 (a superoxide degradation catalyst and nitric oxide donor) improves pulmonary function in a sheep model of septic shock caused by Pseudomonas aeruginosa and smoke inhalation. METHODS: Eleven female sheep were prepared surgically and randomly assigned to a treatment group (n = 5) or a control group (n = 6) after inhalation of cooled cotton smoke and airway instillation of live P. aeruginosa (2.5 × 1011 CFU) by bronchoscope under deep anesthesia and analgesia. The treatment group received an intravenous infusion of a total of 80 mg/kg of R-100 diluted in 500 mL of 5% dextrose. The control group was given 500 mL of 5% dextrose. All animals received intravenous lactated Ringer's solution to maintain a hematocrit level at baseline ± 3%. Blood gas and hemodynamics were measured at baseline and then analyzed every 3 h during the 24-h study period. Results are expressed as mean ± SEM. RESULTS: The treated animals showed significant improvement in their pulmonary gas exchange (PaO2/FiO2 ratio at 24 h: 246 ± 29 vs. 90 ± 40 mmHg control, P < 0.05). Pulmonary arterial pressures were reduced in the treated group (24 h: 26 ± 1 vs. 30 ± 2 cm mmHg control, P < 0.05). The treated animals also had an improved total fluid balance after 24 h (190 ± 45/24 h mL vs. 595 ± 234/24 h mL control, P < 0.05). CONCLUSIONS: Treatment with R-100 improves pulmonary gas exchange and blood oxygenation, and prevents a fluid imbalance in sheep subjected to smoke inhalation and P. aeruginosa.

Severity of Inhalation Injury is Predictive of Alterations in Gas Exchange and Worsened Clinical Outcomes.

Inhalation injury (INH) is present in one third of large burn injuries and increases oxygenation and fluid resuscitation requirements, incidences of pulmonary complications, risk for multiple organ dysfunction syndrome (MODS), and overall mortality. Previous studies have demonstrated inconsistent correlation between bronchoscopic evaluation and clinical outcomes. The authors reviewed 161 patients admitted with a diagnosis of INH or underwent diagnostic bronchoscopy for suspected INH over a period of 8.5 years. One hundred one patients had concomitant burn injury and 60 had isolated INH. Seventeen patients had abbreviated injury score (AIS) 0, 81 patients had low-grade injury (AIS 1 and 2), and 63 patients had high-grade injury (AIS 3 and 4). Patients with high-grade INH had worse pulmonary dysfunction, worse oxygenation indices (P = 0.01) and plasma carboxyhemoglobin (COHgb; P < 0.01) on admission, increased fluid requirements (P < 0.01 at 24 hours; P = 0.04 at 48 hours), MODS (P = 0.04), pneumonia (P < 0.01), acute respiratory distress syndrome (P = 0.01 at 48 hours), fewer 28-day ventilator-free days (P < 0.01), greater ventilator dependence (P = 0.03), and longer length of stay (P < 0.01). Multivariate analyses demonstrated increased risk of MODS (P = 0.03), acute respiratory distress syndrome at 48 hours (P < 0.01), pneumonia (P = 0.01), prolonged ventilator dependence (P = 0.03), and a trend toward mortality (P = 0.08) with higher AIS groups. More severe INH correlates with early oxygenation impairments and is associated with more complicated hospitalization, fluid resuscitation requirements, and ventilation demands. Severe INH is associated with and predictive of increased morbidity and mortality.

A model of recovery from inhalation injury and cutaneous burn in ambulatory swine.

Inhalation injury commonly accompanies thermal injury, increasing the likelihood of mortality and multiple organ dysfunction (MOD). Large animal models have given important insight into the pathophysiology of this injury; however recapitulating late MOD has remained difficult. The current report describes experiments using a smoke inhalation and burn model, with follow-up of ambulatory swine for 14days with bronchoscopy, CT scanning, and bronchoalveolar lavage fluid (BALF)/blood collection. Clinically, animals cleared airway damage in the first several days after-injury. This was mirrored with erythematous airways on day 2 after-injury, which resolved by the end of the experiment, as did parenchymal damage seen on CT. An initial rise in the protein content of BALF immediately after-injury was followed by a dramatic increase in the concentration of leukocytes. Circulating neutrophils increased while lymphocytes decreased; both correlated with cell counts in BALF. IL8 levels in BALF increased 30-fold and remained elevated throughout the experiment. IL1ra increased circulation immediately after-injury, and afterwards in BALF. Other cytokines (TNFα, IL12) transiently increased in BALF (and decreased in circulation) on day 2. Taken together, these results display a remarkable capability for the lungs to recover in the absence of intubation, with further evidence of the role of cytokines such as IL8 and IL1ra. The possible exacerbating effects of clinical practices such as ventilation and bronchoscopies should be considered.

Comprehensive systems biology analysis of a 7-month cigarette smoke inhalation study in C57BL/6 mice.

Smoking of combustible cigarettes has a major impact on human health. Using a systems toxicology approach in a model of chronic obstructive pulmonary disease (C57BL/6 mice), we assessed the health consequences in mice of an aerosol derived from a prototype modified risk tobacco product (pMRTP) as compared to conventional cigarettes. We investigated physiological and histological endpoints in parallel with transcriptomics, lipidomics, and proteomics profiles in mice exposed to a reference cigarette (3R4F) smoke or a pMRTP aerosol for up to 7 months. We also included a cessation group and a switching-to-pMRTP group (after 2 months of 3R4F exposure) in addition to the control (fresh air-exposed) group, to understand the potential risk reduction of switching to pMRTP compared with continuous 3R4F exposure and cessation. The present manuscript describes the study design, setup, and implementation, as well as the generation, processing, and quality control analysis of the toxicology and 'omics' datasets that are accessible in public repositories for further analyses.

OXIDATIVE STRESS IN A RAT MODEL OF COTTON SMOKE INHALATION-INDUCED PULMONARY INJURY.

BACKGROUND: Smoke inhalation injury refers to airway and lung parenchyma injury and general chemical damage caused by inhaling toxic gases and substances. The aim of this study was to explore the oxidative stress mechanism of cotton smoke inhalation-induced pulmonary injury in a rat model. MATERIALS AND METHODS: Eighteen male Sprague-Dawley rats were randomly divided into control group, 6 h group, and 24 h group (six rats in each group), which duplicated previous rat cotton smoke-inhalation injury models. Rats in 6 h and 24 h groups were euthanised at 6 h and 24 h after smoke inhalation, respectively. ELISA method was used to detect indicators in the rats' lung tissue. Quantitative iNOS mRNA and γ-GCS mRNA measurements were performed using a fluorescence PCR method. RESULTS: The concentrations of MDA, NO, iNOS, γ-GCS, iNOS mRNA, and the relative expression of γ-GCS mRNA in the rats' lung tissues in 6 h and 24 h groups were higher than control group (P < 0.05), and the concentration of NO and relative expressions of iNOS mRNA and γ-GCS mRNA in 24 h group were significantly higher than 6 h group (P < 0.05). The concentrations of GSH in 24 h and 6 h groups were significantly lower than control group (P < 0.05), and that in 24 h group was even significantly lower than 6 h group (P < 0.05). CONCLUSION: In rats with cotton smoke inhalation-induced pulmonary injury, the increased iNOS mRNA transcription can cause increase of iNOS synthesis and promotion of NO synthesis. The increased γ-GCS mRNA transcription can cause increase of γ-GCS synthesis and but decrease of GSH concentration. The activation of the antioxidant system is insufficient to combat oxidative stress damage. So the oxidant/antioxidant system is imbalanced, leading to gradual aggravation of lung injury.

Diagnosis and management of inhalation injury: an updated review.

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

[Effects of two kinds of lung recruitment maneuvers on the correlated indexes of dogs with severe smoke inhalation injury].

OBJECTIVE: To observe and compare the effects of two kinds of lung recruitment maneuvers, namely sustained inflation (SI) and incremental positive end-expiratory pressure (PEEP) (IP) on oxygenation, respiratory mechanics, and hemodynamics of dogs with severe smoke inhalation injury. METHODS: After being treated with conventional mechanical ventilation, 12 dogs were inflicted with severe smoke inhalation injury. They were divided into group SI and group IP according to the random number table, with 6 dogs in each group. Dogs in group SI were subjected to continuous positive airway pressure ventilation, with inspiratory pressure of 25 cmH2O (1 cmH2o = 0. 098 kPa), and it was sustained for 20 s. PEEP level in group IP was gradually increased by 5 cmH2O every 5 min up to 25 cmH2O, and then it was decreased by 5 cmH2O every 5 min until reaching 2-3 cmH2O. Then the previous ventilation mode was resumed in both groups for 8 hours. Blood gas analysis (pH value, PaO2, and PaCO2), oxygenation index (OI), respiratory mechanics parameters [peak inspiratory pressure (PIP), mean airway pressure, and dynamic lung compliance], and hemodynamic parameters [heart rate, mean arterial pressure (MAP), pulmonary arterial pressure (PAP), and cardiac output (CO)] were recorded or calculated before injury, immediately after injury, and at post ventilation hour (PVH) 2, 4, 6, 8. Data were processed with analysis of variance of repeated measurement and LSD-t test. RESULTS: (1) At PVH 6 and 8, pH values of dogs in group SI were significantly lower than those in group IP (with t values respectively 2. 431 and 2. 261, P values below 0.05); PaO2 levels in group SI [(87 ± 24), (78 ± 14) mmHg, 1 mmHg =0. 133 kPa] were lower than those in group IP [ (114 ± 18) , (111 ± 17) mmHg, with t values respectively 2. 249 and 3.671, P <0.05 or P <0.01]; OI values in group SI were significantly higher than those in group IP (with t values respectively 2.363 and 5.010, P <0.05 or P <0.01). No significant differences were observed in PaCO2 level within each group or between the two groups (with t values from 0. 119 to 1. 042, P values above 0.05). Compared with those observed immediately after injury, the pH values were significantly lowered (except for dogs in group IP at PVH 6 and 8, with t values from 2.292 to 3.222, P <0.05 or P <0.01), PaO2 levels were significantly elevated (with t values from 4. 443 to 6.315, P <0.05 or P <0.01), and OI values were significantly lowered (with t values from 2.773 to 9.789, P <0.05 orP <0.01) in both groups at all the treatment time points. (2) The PIP level at each time point showed no significant differences between two groups (with t values from 0. 399 to 1. 167, P values above 0. 05). At PVH 4 and 8, the mean airway .pressure values of dogs in group SI were significantly higher than those in group IP (with t values respectively 1.926 and 1. 190, P values below 0.05). At PVH 4, 6, and 8, the dynamic lung compliance levels of dogs in group SI [(9.5 ± 1.9), (12.8 ± 2. 1), (13. 1 ± 1.8) mL/cmH2O] were significantly lower than those in group IP [(11.6 ± 1.2), (15.4 ± 1.8), (14.9 ± 0.8) mL/cmH2O], with t values respectively 2. 289, 2. 303, 2. 238, P values below 0.05. Compared with those observed immediately after injury, PIP and the mean airway pressure values of dogs in two groups were significantly lowered at each treatment time point (with t values from 2. 271 to 7. 436, P <0. 05 or P < 0.01); the dynamic lung compliance levels were significantly elevated in both groups at PVH 6 and 8 (with t values from 2. 207 to 4. 195, P < 0.05 or P <0.01). (3) Heart rate, MAP, and PAP levels at each time point between two groups showed no significant differences (with t values from 0. 001 to 1. 170, P values above 0. 05). At PVH 4, 6, and 8, CO levels in group IP [(0. 6 + 0. 3), (0. 6 + 0. 4), (0. 5 + 0. 7) L/min] were significantly lower than those in group SI [(1.5 0.7), (1.8 + 1.1), (1.6 +0.9) L/min], with t values respectively 3. 028, 2.511, 2.363, P values below 0.05. Compared with that observed immediately after injury, CO level in group IP was significantly lowered at PVH 4, 6, or 8 (with t values respectively 2. 363, 2. 302, 2. 254, P values below 0. 05). CONCLUSIONS: Both lung recruitment maneuvers can effectively improve oxygenation and lung compliance of dogs with severe smoke inhalation injury. IP is more effective in improving lung compliance, while SI shows less impact on the hemodynamic parameters.

Antithrombin attenuates myocardial dysfunction and reverses systemic fluid accumulation following burn and smoke inhalation injury: a randomized, controlled, experimental study.

INTRODUCTION: We hypothesized that maintaining physiological plasma levels of antithrombin attenuates myocardial dysfunction and inflammation as well as vascular leakage associated with burn and smoke inhalation injury. Therefore, the present prospective, randomized experiment was conducted using an established ovine model. METHODS: Following 40% of total body surface area, third degree flame burn and 4 × 12 breaths of cold cotton smoke, chronically instrumented sheep were randomly assigned to receive an intravenous infusion of 6 IU/kg/h recombinant human antithrombin (rhAT) or normal saline (control group; n = 6 each). In addition, six sheep were designated as sham animals (not injured, continuous infusion of vehicle). During the 48 h study period the animals were awake, mechanically ventilated and fluid resuscitated according to standard formulas. RESULTS: Compared to the sham group, myocardial contractility was severely impaired in control animals, as suggested by lower stroke volume and left ventricular stroke work indexes. As a compensatory mechanism, heart rate increased, thereby increasing myocardial oxygen consumption. In parallel, myocardial inflammation was induced via nitric oxide production, neutrophil accumulation (myeloperoxidase activity) and activation of the p38-mitogen-activated protein kinase pathway resulting in cytokine release (tumor necrosis factor-alpha, interleukin-6) in control vs. sham animals. rhAT-treatment significantly attenuated these inflammatory changes leading to a myocardial contractility and myocardial oxygen consumption comparable to sham animals. In control animals, systemic fluid accumulation progressively increased over time resulting in a cumulative positive fluid balance of about 4,000 ml at the end of the study period. Contrarily, in rhAT-treated animals there was only an initial fluid accumulation until 24 h that was reversed back to the level of sham animals during the second day. CONCLUSIONS: Based on these findings, the supplementation of rhAT may represent a valuable therapeutic approach for cardiovascular dysfunction and inflammation after burn and smoke inhalation injury.

Inhalation injury: epidemiology, pathology, treatment strategies.

Lung injury resulting from inhalation of smoke or chemical products of combustion continues to be associated with significant morbidity and mortality. Combined with cutaneous burns, inhalation injury increases fluid resuscitation requirements, incidence of pulmonary complications and overall mortality of thermal injury. While many products and techniques have been developed to manage cutaneous thermal trauma, relatively few diagnosis-specific therapeutic options have been identified for patients with inhalation injury. Several factors explain slower progress for improvement in management of patients with inhalation injury. Inhalation injury is a more complex clinical problem. Burned cutaneous tissue may be excised and replaced with skin grafts. Injured pulmonary tissue must be protected from secondary injury due to resuscitation, mechanical ventilation and infection while host repair mechanisms receive appropriate support. Many of the consequences of smoke inhalation result from an inflammatory response involving mediators whose number and role remain incompletely understood despite improved tools for processing of clinical material. Improvements in mortality from inhalation injury are mostly due to widespread improvements in critical care rather than focused interventions for smoke inhalation.Morbidity associated with inhalation injury is produced by heat exposure and inhaled toxins. Management of toxin exposure in smoke inhalation remains controversial, particularly as related to carbon monoxide and cyanide. Hyperbaric oxygen treatment has been evaluated in multiple trials to manage neurologic sequelae of carbon monoxide exposure. Unfortunately, data to date do not support application of hyperbaric oxygen in this population outside the context of clinical trials. Cyanide is another toxin produced by combustion of natural or synthetic materials. A number of antidote strategies have been evaluated to address tissue hypoxia associated with cyanide exposure. Data from European centers supports application of specific antidotes for cyanide toxicity. Consistent international support for this therapy is lacking. Even diagnostic criteria are not consistently applied though bronchoscopy is one diagnostic and therapeutic tool. Medical strategies under investigation for specific treatment of smoke inhalation include beta-agonists, pulmonary blood flow modifiers, anticoagulants and antiinflammatory strategies. Until the value of these and other approaches is confirmed, however, the clinical approach to inhalation injury is supportive.