Dynamics of acute respiratory distress syndrome development due to smoke inhalation injury: Implications for prolonged field care.

BACKGROUND: Smoke inhalation injury (SII) causes 30% to 40% mortality and will increase as a cause of death during prolonged field care. We used a combat relevant model of acute respiratory distress syndrome due to SII to study temporal changes in ventilation-perfusion (V/Q) matching, computed tomography (CT) scan data, and histopathology and hypothesized that SII leads to increase in shunt (Qshunt), V/Q mismatch, lung consolidation, and diffuse alveolar damage. METHODS: Swine received severe SII and airway pressure release ventilation (APRV, n = 6), or conventional ARDSNet mechanical ventilation (MV) (CMV, n = 8). A control group without injury received volume controlled MV (CTRL, n = 6), The multiple inert gas elimination technique and CT were performed at baseline (BL), 0.5 hours, 1 hours, 2 hours, 24 hours, and 48 hours after injury. Diffuse alveolar damage scoring was performed post mortem. Significance at p less than 0.05: APRV versus CTRL; CMV versus CTRL; APRV versus CMV*; denotes changes versus BL. RESULTS: (1) SII caused increases in Qshunt more so in APRV than CMV group. Qshunt did not change in CTRL. (2) PaO2-to-FIO2 ratio (PFR) was lower in APRV versus CTRL at 2 hours (375 ± 62‡ vs. 549 ± 40) and 24 hours (126 ± 34‡* vs. 445 ± 5) and 48 hours (120 ± 41‡& vs. 430 ± 13). In CMV animals, PFR was lower versus CTRL and BL at 24 hours (238 ± 33) and 48 hours (98 ± 27). Qshunt correlated with PFR (r = 0.75, p < 0.0001, APRV and (r = 0.65, p < 0.0001, CMV). CT showed decrease in normally aerated lung, while poorly and nonaerated lung increased. CONCLUSION: Smoke inhalation injury leads to early development of shunt, V/Q mismatch, lung consolidation, and diffuse alveolar damage. These data substantiate the need for new point of injury interventions in the prolonged field care setting. LEVEL OF EVIDENCE: Animal research.

Point-of-care endoscopic optical coherence tomography detects changes in mucosal thickness in ARDS due to smoke inhalation and burns.

BACKGROUND: The prevalence of acute respiratory distress syndrome (ARDS) in mechanically ventilated burn patients is 33%, with mortality varying from 11-46% depending on ARDS severity. Despite the new Berlin definition for ARDS, prompt bedside diagnosis is lacking. We developed and tested a bedside technique of fiberoptic-bronchoscopy-based optical coherence tomography (OCT) measurement of airway mucosal thickness (MT) for diagnosis of ARDS following smoke inhalation injury (SII) and burns. METHODS: 16 female Yorkshire pigs received SII and 40% thermal burns. OCT MT and PaO2-to-FiO2 ratio (PFR) measurements were taken at baseline, after injury, and at 24, 48, and 72h after injury. RESULTS: Injury led to thickening of MT which was sustained in animals that developed ARDS. Significant correlations were found between MT, PFR, peak inspiratory pressure (PIP), and total infused fluid volume. CONCLUSIONS: OCT is a useful tool to quantify MT changes in the airway following SII and burns. OCT may be effective as a diagnostic tool in the early stages of SII-induced ARDS and should be tested in humans.

Resuscitative endovascular balloon occlusion of the aorta (REBOA): Comparison with immediate transfusion following massive hemorrhage in swine.

BACKGROUND: Resuscitative endovascular balloon occlusion of the aorta (REBOA) is less invasive than emergency department thoracotomy for the treatment of massive hemorrhage. We evaluated the effects of REBOA on carotid blood flow (Qcarotid) in a porcine model of massive hemorrhage. We hypothesized that REBOA restores Qcarotid faster than reinfusion of blood. METHODS: Spontaneously breathing sedated Sinclair pigs underwent exponential hemorrhage of 65% total blood volume in 1 hour. They were randomized into three groups. Positive control (PC, n = 7) underwent immediate transfusion of shed blood. REBOA (n = 21) received a novel 7 Fr ER-REBOA catheter (Pryor Medical, Arvada, CO) placed into aortic Zone 1 via a femoral artery introducer for 30 minutes or 60 minutes, with transfusion either after deflation or midway through inflation. Negative control (n = 7) received no resuscitation. Qcarotid was recorded continuously using an ultrasonic flow probe. Survival and time between Qcarotid, min and both a stable maximal value (Qcarotid, max) and restoration of baseline flow (Qcarotid, new BL) were compared by Kaplan-Meier analysis. RESULTS: Median time to Qcarotid, max was 3.0 minutes in the REBOA group versus 9.6 minutes in the control group (p = 0.006). Median time to Qcarotid, new BL was 6.0 minutes in the REBOA group versus 20.5 minutes in the PC group (p = 0.11). Slope of the linear regression between Qcarotid, min and Qcarotid, new BL was 16.7 in REBOA and 10.4 in PC (p = 0.31). Four-hour survival was 95% (20 of 21) in the REBOA group versus 71% (5 of 7) in the PC group (p = 0.06) and 0% in the negative control group. CONCLUSION: REBOA resulted in the restoration of Qcarotid ("cerebrovascular resuscitation") at least as rapidly as retransfusion of shed blood, with equivalent 4-hour survival. Further studies of REBOA, to include mitigation of end-organ effects and longer follow-up, are needed.

Comparison of virtual bronchoscopy to fiber-optic bronchoscopy for assessment of inhalation injury severity.

PURPOSE: Compare virtual bronchoscopy (VB) to fiberoptic bronchoscopy (FOB) for scoring smoke inhalation injury (SII). METHODS: Swine underwent computerized tomography (CT) with VB and FOB before (0) and 24 and 48 h after SII. VB and FOB images were scored by 5 providers off line. RESULTS: FOB and VB scores increased over time (p<0.001) with FOB scoring higher than VB at 0 (0.30±0.79 vs. 0.03±0.17), 24 h (4.21±1.68 vs. 2.47±1.50), and 48h (4.55±1.83 vs. 1.94±1.29). FOB and VB showed association with PaO2-to-FiO2 ratios (PFR) with areas under receiver operating characteristic curves (ROC): for PFR≤300, VB 0.830, FOB 0.863; for PFR≤200, VB 0.794, FOB 0.825; for PFR≤100, VB 0.747, FOB 0.777 (all p<0.001). FOB showed 80.3% specificity, 77% sensitivity, 88.8% negative-predictive value (NPV), and 62.3% positive-predictive value (PPV) for PFR≤300 and VB showed 67.2% specificity, 85.5% sensitivity, 91.3% NPV, and 53.4% PPV. CONCLUSIONS: VB provided similar injury severity scores to FOB, correlated with PFR, and reliably detected airway narrowing. VB performed during admission CT may be a useful screening tool specifically to demonstrate airway narrowing induced by SII.

Development and resuscitation of a sedated, mature male miniature swine severe hemorrhage model.

BACKGROUND: A sedated, mature male miniature swine hemorrhage model has been specifically developed to evaluate resuscitation products for the Defense Advanced Research Projects Agency Surviving Blood Loss program. METHODS: Animals were placed in a sling, sedated with midazolam, and hemorrhaged 60% of estimated blood volume (∼39 mL/kg) exponentially for 1 hour with no resuscitation (control; n = 16). An additional 26 swine were treated similarly, then resuscitated with 1 mL/kg/min of Hextend to a systolic blood pressure of either 65 mm Hg ± 2 mm Hg (n = 7) or 80 mm Hg ± 5 mm Hg (n = 7) and with 17ß-estradiol (E2) at 1 mg/kg (n = 6) or 10 mg/kg (n = 6). Animals were observed for 3 hours with periodic blood sampling. Survival times for the two E2 groups were not significantly different (p = 0.59); therefore, the groups were combined for comparison with control. RESULTS: Hemorrhage resulted in a characteristic hypotension and metabolic acidosis. Survival time for the control swine was 64 minutes ± 11.5 minutes with a 6% survival at 180 minutes. The 180 minutes Hextend survival was 86% for 65 mm Hg and 100% for 80 mm Hg. E2 survival was 125 minutes ± 15.3 minutes, significantly different from control (p = 0.01), but E2 survival of 25% at 180 minutes was not different from control. CONCLUSION: A sedated, sexually mature male miniature swine severe hemorrhage model has been successfully developed, resuscitated with Hextend and used to evaluate E2 as a small volume resuscitation product.

Dynamic changes in shunt and ventilation-perfusion mismatch following experimental pulmonary contusion.

The objective of this study was to investigate early changes in oxygenation by means of the multiple inert gas elimination technique and in coagulation by means of thromboelastography (TEG) after right-sided pulmonary contusion (PC) in swine. Anesthetized swine (group 1; n = 8) sustained a right-chest PC by a captive-bolt stunner. Multiple inert gas elimination technique, TEG, and thoracic computed tomography (CT) scans were performed before and 10, 30, 60, and 120 min after injury. Three-dimensional CT scan reconstruction enabled measurement of volumes of poorly (Vol(Poor)) and nonaerated (Vol(Non)) lung. Eight animals (group 0) were used as uninjured controls. Pulmonary contusion led to sustained tachycardia and transient hypotension. Partial pressure of arterial oxygen (PaO2) decreased from 83.9 +/- 4.2 mmHg at baseline to 51.3 +/- 2.8 mmHg 10 min after PC (P < 0.001). Vol(Poor) and Vol(Non) on the right increased significantly after PC, followed by gradual progression in injury marked by decreased Vol(Poor) and increased Vol(Non). By the multiple inert gas elimination technique, blood flow to the true shunt compartment increased from 4.4% +/- 1.0% at baseline to 21.2% +/- 4.9% 10 min after PC, P < 0.001, peaked at 33.2% +/- 7.5% 30 min after PC, P < 0.001, and remained significantly higher compared with controls. Transient increase in blood flow to low and very low ventilation-perfusion (V/Q) compartments was also seen. Clot reaction time and formation rate by TEG increased at 2 h after PC. True shunt is the major cause of hypoxemia after PC, but V/Q mismatch also contributes significantly early after injury. By CT, PC leads to significant loss of functional lung volume on the side of injury. A mild hypocoagulable state was identified 2 h after injury.

Ventilation-perfusion relationships following experimental pulmonary contusion.

Ventilation-perfusion changes after right-sided pulmonary contusion (PC) in swine were investigated by means of the multiple inert gas elimination technique (MIGET). Anesthetized swine (injury, n = 8; control, n = 6) sustained a right-chest PC by a captive-bolt apparatus. This was followed by a 12-ml/kg hemorrhage, resuscitation, and reinfusion of shed blood. MIGET and thoracic computed tomography (CT) were performed before and 6 h after injury. Three-dimensional CT scan reconstruction enabled determination of the combined fractional volume of poorly aerated and non-aerated lung tissue (VOL), and the mean gray-scale density (MGSD). Six hours after PC in injured animals, Pa(O(2)) decreased from 234.9 +/- 5.1 to 113.9 +/- 13.0 mmHg. Shunt (Q(S)) increased (2.7 +/- 0.4 to 12.3 +/- 2.2%) at the expense of blood flow to normal ventilation/perfusion compartments (97.1 +/- 0.4 to 87.4 +/- 2.2%). Dead space ventilation (V(D)/V(T)) increased (58.7 +/- 1.7% to 67.2 +/- 1.2%). MGSD increased (-696.7 +/- 6.1 to -565.0 +/- 24.3 Hounsfield units), as did VOL (4.3 +/- 0.5 to 33.5 +/- 3.2%). Multivariate linear regression of MGSD, VOL, V(D)/V(T), and Q(S) vs. Pa(O(2)) retained VOL and Q(S) (r(2) = .835) as independent covariates of Pa(O(2)). An increase in Q(S) characterizes lung failure 6 h after pulmonary contusion; Q(S) and VOL correlate independently with Pa(O(2)).

Acute respiratory distress syndrome secondary to inhalation of chlorine gas in sheep.

BACKGROUND: Toxic industrial chemicals (TICs) are potential terrorist weapons. Several TICs, such as chlorine, act primarily on the respiratory tract, but knowledge of the pathophysiology and treatment of these injuries is inadequate. This study aims to characterize the acute respiratory distress syndrome (ARDS) caused by chlorine gas (Cl2) inhalation in a large-animal model. METHODS: Anesthetized female sheep were ventilated with 300 L of a Cl2/air/oxygen mixture for 30 minutes. In phase 1 (n = 35), doses were 0 ppm (Group 1, n = 6); 120 ppm (Group 2, n = 6); 240 to 350 ppm (Group 3, n = 11); and 400 to 500 ppm (Group 4, n = 12). In phase 2 (n = 17), doses were 0 ppm (Group 5, n = 5); 60 ppm (Group 6, n = 5); and 90 ppm (Group 7, n = 7), and the multiple inert gas elimination technique (MIGET) was used to characterize the etiology of hypoxemia. Computed tomography (CT) scans were performed daily for all animals. RESULTS: In Phase 1, lung function was well maintained in Group 1; Cl2 caused immediate and sustained acute lung injury (PaO2-to-FiO2 ratio, PFR<3.0) in Group 2 and ARDS (PFR<2.0) in Groups 3 and 4. All animals in Groups 1 and 2 survived 96 hours. Kaplan-Meier analysis showed dose-related differences in survival (log-rank test, p < 0.0001). Logistic regression identified 280 ppm as the lethal dose 50%. CT and histopathology demonstrated lesions of both small airways and alveoli. In Phase 2, MIGET showed diversion of blood flow from normal to true-shunt lung compartments and, transiently, to poorly ventilated compartments. CONCLUSIONS: Cl2 causes severe, dose-related lung injury, with features seen in both smoke inhalation and in ARDS secondary to systemic disease. This model will be used to test new therapeutic modalities.

Assessment of oxidative stress in lungs from sheep after inhalation of wood smoke.

To elucidate potential dose-dependent mechanisms associated with wood smoke inhalation injury, the present study evaluated antioxidant status and the extent of pulmonary injury in sheep after graded exposure to smoke. Adult, male sheep (n=4-5 per group) were anesthetized and received 0, 5, 10 or 16 units of cooled western pine bark smoke, corresponding to 0, 175, 350 and 560 s, respectively, of smoke dwell time in the airways and lung. Smoke was mixed at a 1:1 ratio with 100% O2 to minimize hypoxia. Plasma and expired breath samples were collected pre-smoke, and 6, 12, 18, 24, 36 and 48 h after smoke exposure. Sheep were euthanatized 48 h after smoke exposure and lung and airway sections were evaluated histologically for injury and biochemically for indices of oxidative stress. Plasma thiobarbituric acid reactive substances (TBARS) were 66 and 69% higher than controls after moderate and severe smoke exposure at 48 h, whereas total antioxidant potential was not statistically different among groups at any time after exposure. Lung TBARS showed a dose-dependent response to smoke inhalation and were approximately 2-, 3- and 4-fold higher, respectively, than controls after exposure to 5, 10 and 16 units of smoke. Lung myeloperoxidase (MPO) activity was also higher in smoke-exposed animals than controls, and MPO activity was markedly elevated (19- and 22-fold higher than controls in right apical and medial lobes) in response to severe smoke exposure. Smoke exposure also induced a dose-dependent injury to tracheobronchial epithelium and lung parenchyma. Taken together these data show that few indices of oxidative stress responded in a dose-dependent manner to graded doses of smoke inhalation, although most of the indices measured in lung were affected by the highest dose of smoke. Additional time course studies are necessary to determine whether these oxidants are a cause or a consequence of the airway and lung injury associated with exposure to wood smoke.