A novel large animal model of smoke inhalation-induced acute respiratory distress syndrome.

BACKGROUND: Acute respiratory distress syndrome (ARDS) is multifactorial and can result from sepsis, trauma, or pneumonia, amongst other primary pathologies. It is one of the major causes of death in critically ill patients with a reported mortality rate up to 45%. The present study focuses on the development of a large animal model of smoke inhalation-induced ARDS in an effort to provide the scientific community with a reliable, reproducible large animal model of isolated toxic inhalation injury-induced ARDS. METHODS: Animals (n = 21) were exposed to smoke under general anesthesia for 1 to 2 h (median smoke exposure = 0.5 to 1 L of oak wood smoke) after the ultrasound-guided placement of carotid, pulmonary, and femoral artery catheters. Peripheral oxygen saturation (SpO2), vital signs, and ventilator parameters were monitored throughout the procedure. Chest x-ray, carotid, femoral and pulmonary artery blood samples were collected before, during, and after smoke exposure. Animals were euthanized and lung tissue collected for analysis 48 h after smoke inhalation. RESULTS: Animals developed ARDS 48 h after smoke inhalation as reflected by a decrease in SpO2 by approximately 31%, PaO2/FiO2 ratio by approximately 208 (50%), and development of bilateral, diffuse infiltrates on chest x-ray. Study animals also demonstrated a significant increase in IL-6 level, lung tissue injury score and wet/dry ratio, as well as changes in other arterial blood gas (ABG) parameters. CONCLUSIONS: This study reports, for the first time, a novel large animal model of isolated smoke inhalation-induced ARDS without confounding variables such as cutaneous burn injury. Use of this unique model may be of benefit in studying the pathophysiology of inhalation injury or for development of novel therapeutics.

Development of a multi-patient ventilator circuit with validation in an ARDS porcine model.

PURPOSE: The COVID-19 pandemic threatens our current ICU capabilities nationwide. As the number of COVID-19 positive patients across the nation continues to increase, the need for options to address ventilator shortages is inevitable. Multi-patient ventilation (MPV), in which more than one patient can use a single ventilator base unit, has been proposed as a potential solution to this problem. To our knowledge, this option has been discussed but remains untested in live patients with differing severity of lung pathology. METHODS: The objective of this study was to address ventilator shortages and patient stacking limitations by developing and validating a modified breathing circuit for two patients with differing lung compliances using simple, off-the-shelf components. A multi-patient ventilator circuit (MPVC) was simulated with a mathematical model and validated with four animal studies. Each animal study had two human-sized pigs: one healthy and one with lipopolysaccharide (LPS) induced ARDS. LPS was chosen because it lowers lung compliance similar to COVID-19. In a previous study, a control group of four pigs was given ARDS and placed on a single patient ventilation circuit (SPVC). The oxygenation of the MPVC ARDS animals was then compared to the oxygenation of the SPVC animals. RESULTS: Based on the comparisons, similar oxygenation and morbidity rates were observed between the MPVC ARDS animals and the SPVC animals. CONCLUSION: As healthcare systems worldwide deal with inundated ICUs and hospitals from pandemics, they could potentially benefit from this approach by providing more patients with respiratory care.

Treatment of a Rat Model of LPS-Induced ARDS via Peritoneal Perfusion of Oxygen Microbubbles.

Acute respiratory distress syndrome (ARDS) is a serious respiratory condition that occurs in approximately 10% of patients entering intensive care units around the world, affecting nearly 190,000 patients annually in the United States. Owing to the severity of the condition, conventional methods of oxygenation are often insufficient. However, current alternate methods of oxygenation are associated with contraindications and a mortality rate near 50%. Therefore, a need exists for a safer and more effective method of oxygenation for patients with ARDS. In this work, the feasibility of using intraperitoneal perfusions of oxygen microbubbles-peritoneal microbubble oxygenation (PMO)-to treat lipopolysaccharide-induced ARDS was explored with the objective of showing restoration of normoxic conditions after a single bolus infusion of oxygen microbubbles. Male Wistar rats induced with ARDS via lipopolysaccharide inhalation were treated with PMO at 12-h intervals over a period of 48 h. Their physiological responses were monitored throughout the study, after which necropsy was performed. Response data were then compared with saline control and untreated groups. We conclude that rats experiencing moderate to severe ARDS that were treated with PMO experienced a survival rate 37% higher than animals not given treatment and exhibited increased peripheral blood oxygen saturation when compared with untreated and saline-treated groups. Moreover, those treated with PMO experienced a lower lung wet/dry ratio and less severe lung pathology, indicating a surprising improvement in lung health. Overall, this study demonstrates the ability of PMO to deliver life-sustaining supplemental oxygen to rats suffering from ARDS and warrants further work toward clinical translation.

Neutrophil-mediated Inflammatory Plasminogen Degradation, Rather Than High Plasminogen-Activator Inhibitor-1, May Underly Failures and Inefficiencies of Intrapleural Fibrinolysis.

BACKGROUND: Complex pleural space infections often require treatment with multiple doses of intrapleural tissue plasminogen activator (tPA) and deoxyribonuclease, with treatment failure frequently necessitating surgery. Pleural infections are rich in neutrophils, and neutrophil elastase degrades plasminogen, the target substrate of tPA, that is required to generate fibrinolysis. We hypothesized that pleural fluid from patients with pleural space infection would show high elastase activity, evidence of inflammatory plasminogen degradation, and low fibrinolytic potential in response to tPA that could be rescued with plasminogen supplementation. RESEARCH QUESTION: Does neutrophil elastase degradation of plasminogen contribute to intrapleural fibrinolytic failure? STUDY DESIGN AND METHODS: We obtained infected pleural fluid and circulating plasma from hospitalized adults (n = 10) with institutional review board approval from a randomized trial evaluating intrapleural fibrinolytics vs surgery for initial management of pleural space infection. Samples were collected before the intervention and on days 1, 2, and 3 after the intervention. Activity assays, enzyme-linked immunosorbent assays, and Western blot analysis were performed, and turbidimetric measurements of fibrinolysis were obtained from pleural fluid with and without exogenous plasminogen supplementation. Results are reported as median (interquartile range) or number (percentage) as appropriate, with an α value of .05. RESULTS: Pleural fluid elastase activity was more than fourfold higher (P = .02) and plasminogen antigen levels were more than threefold lower (P = .04) than their corresponding plasma values. Pleural fluid Western blot analysis demonstrated abundant plasminogen degradation fragments consistent with elastase degradation patterns. We found that plasminogen activator inhibitor 1 (PAI-1), the native tPA inhibitor, showed high antigen levels before the intervention, but the overwhelming majority of this PAI-1 (82%) was not active (P = .003), and all PAI-1 activity was lost by day 2 after the intervention in patients receiving intrapleural tPA and deoxyribonuclease. Finally, using turbidity clot lysis assays, we found that the pleural fluid of 9 of 10 patients was unable to generate a significant fibrinolytic response when challenged with tPA and that plasminogen supplementation rescued fibrinolysis in all patients. INTERPRETATION: Our findings suggest that inflammatory plasminogen deficiency, not high PAI-1 activity, is a significant contributor to intrapleural fibrinolytic failure. TRIAL REGISTRY: ClinicalTrials.gov; No.: NCT03583931; URL: www. CLINICALTRIALS: gov.

Intraperitoneal oxygen microbubble therapy: A novel approach to enhance systemic oxygenation in a smoke inhalation model of acute hypoxic respiratory failure.

Background: Patients suffering from severe acute respiratory distress syndrome (ARDS) face limited therapeutic options and alarmingly high mortality rates. Refractory hypoxemia, a hallmark of ARDS, often necessitates invasive and high-risk treatments. Oxygen microbubbles (OMB) present a promising approach for extrapulmonary oxygenation, potentially augmenting systemic oxygen levels without exposing patients to significant risks. Methods: Rats with severe, acute hypoxemia secondary to wood smoke inhalation (SI) received intraperitoneal (IP) bolus injections of escalating weight-by-volume (BW/V) OMB doses or normal saline to determine optimal dosage and treatment efficacy. Subsequently, a 10 % BW/V OMB bolus or saline was administered to a group of SI rats and a control group of healthy rats (SHAM). Imaging, vital signs, and laboratory studies were compared at baseline, post-smoke inhalation, and post-treatment. Histological examination and lung tissue wet/dry weight ratios were assessed at study conclusion. Results: Treatment with various OMB doses in SI-induced acute hypoxemia revealed that a 10 % BW/V OMB dose significantly augmented systemic oxygen levels while minimizing dose volume. The second set of studies demonstrated a significant increase in partial pressure of arterial oxygen (PaO2) and normalization of heart rate with OMB treatment in the SI group compared to saline treatment or control group treatment. Conclusions: This study highlights the successful augmentation of systemic oxygenation following OMB treatment in a small animal model of severe hypoxemia. OMB therapy emerges as a novel and promising treatment modality with immense translational potential for oxygenation support in acute care settings.

Colonic oxygen microbubbles augment systemic oxygenation and CO2 removal in a porcine smoke inhalation model of severe hypoxia.

Inhalation injury can lead to pulmonary complications resulting in the development of respiratory distress and severe hypoxia. Respiratory distress is one of the major causes of death in critically ill patients with a reported mortality rate of up to 45%. The present study focuses on the effect of oxygen microbubble (OMB) infusion via the colon in a porcine model of smoke inhalation-induced lung injury. Juvenile female Duroc pigs (n = 6 colonic OMB, n = 6 no treatment) ranging from 39 to 51 kg in weight were exposed to smoke under general anesthesia for 2 h. Animals developed severe hypoxia 48 h after smoke inhalation as reflected by reduction in SpO2 to 66.3 ± 13.1% and PaO2 to 45.3 ± 7.6 mmHg, as well as bilateral diffuse infiltrates demonstrated on chest X-ray. Colonic OMB infusion (75-100 mL/kg dose) resulted in significant improvements in systemic oxygenation as demonstrated by an increase in PaO2 of 13.2 ± 4.7 mmHg and SpO2 of 15.2 ± 10.0% out to 2.5 h, compared to no-treatment control animals that experienced a decline in PaO2 of 8.2 ± 7.9 mmHg and SpO2 of 12.9 ± 18.7% over the same timeframe. Likewise, colonic OMB decreased PaCO2 and PmvCO2 by 19.7 ± 7.6 mmHg and 7.6 ± 6.7 mmHg, respectively, compared to controls that experienced increases in PaCO2 and PmvCO2 of 17.9 ± 11.7 mmHg and 18.3 ± 11.2 mmHg. We conclude that colonic delivery of OMB therapy has potential to treat patients experiencing severe hypoxemic respiratory failure.

Testing oxygenated microbubbles via intraperitoneal and intrathoracic routes on a large pig model of LPS-induced acute respiratory distress syndrome.

With a mortality rate of 46% before the onset of COVID-19, acute respiratory distress syndrome (ARDS) affected 200,000 people in the US, causing 75,000 deaths. Mortality rates in COVID-19 ARDS patients are currently at 39%. Extrapulmonary support for ARDS aims to supplement mechanical ventilation by providing life-sustaining oxygen to the patient. A new rapid-onset, human-sized pig ARDS model in a porcine intensive care unit (ICU) was developed. The pigs were nebulized intratracheally with a high dose (4 mg/kg) of the endotoxin lipopolysaccharide (LPS) over a 2 h duration to induce rapid-onset moderate-to-severe ARDS. They were then catheterized to monitor vitals and to evaluate the therapeutic effect of oxygenated microbubble (OMB) therapy delivered by intrathoracic (IT) or intraperitoneal (IP) administration. Post-LPS administration, the PaO2 value dropped below 70 mmHg, the PaO2 /FiO2 ratio dropped below 200 mmHg, and the heart rate increased, indicating rapidly developing (within 4 h) moderate-to-severe ARDS with tachycardia. The SpO2 and PaO2 of these LPS-injured pigs did not show significant improvement after OMB administration, as they did in our previous studies of the therapy on small animal models of ARDS injury. Furthermore, pigs receiving OMB or saline infusions had slightly lower survival than their ARDS counterparts. The OMB administration did not induce a statistically significant or clinically relevant therapeutic effect in this model; instead, both saline and OMB infusion appeared to lower survival rates slightly. This result is significant because it contradicts positive results from our previous small animal studies and places a limit on the efficacy of such treatments for larger animals under more severe respiratory distress. While OMB did not prove efficacious in this rapid-onset ARDS pig model, it may retain potential as a novel therapy for the usual presentation of ARDS in humans, which develops and progresses over days to weeks.

Endothelial microparticles induce inflammation in acute lung injury.

BACKGROUND: Previously, we have shown that endothelial microparticles (EMPs) injected into mice induce acute lung injury (ALI) [1]. In this study, we hypothesize that EMPs induce ALI by initiating cytokine release in the lung, leading to recruitment and activation of neutrophils. MATERIALS AND METHODS: C57BL/6J male mice (8-10 wk old) were intravenously injected with EMPs (200,000/mL), LPS (2 mg/kg), or both. Bronchoalveolar lavage (BAL) and serum levels of IL-1ß and TNF-α were analyzed by enzyme-linked immunoassay (ELISA). Morphometric analysis was performed on H and E stained lung sections. Myeloperoxidase (MPO) levels were determined via an enzymatic assay and immunofluorescence of stained sections. RESULTS: EMPs led to significantly increased pulmonary and systemic IL-1ß and TNF-α levels, which correlated with increased neutrophil recruitment to the lung. MPO levels in the lungs were increased significantly following injection of EMPs or LPS, compared to PBS. In mice treated with EMPs and LPS either simultaneously or successively, the cytokine and MPO levels were significantly increased over that of either treatment alone. CONCLUSION: EMPs contribute to lung injury through the initiation of a cytokine cascade that increases recruitment of neutrophils and subsequent release of MPO. Furthermore, treatment of mice with both EMPs and LPS induced greater lung injury than either treatment alone, suggesting that EMPs prime the lung for increased injury by other pathogens. Therapies aimed at reducing or blocking EMPs may be a useful strategy for attenuating lung injury.

Rat model of smoke inhalation-induced acute lung injury.

BACKGROUND: Acute lung injury (ALI)/acute respiratory distress syndrome (ARDS) is a lethal disease with limited therapeutic options and an unacceptably high mortality rate. Understanding the complex pathophysiological processes involved in the development of ALI/ARDS is critical for developing novel therapeutic strategies. Smoke inhalation (SI) injury is the leading cause of morbidity and mortality in patients with burn-associated ALI/ARDS; however, to our knowledge few reliable, reproducible models are available for pure SI animal model to investigate therapeutic options for ALI/ARDS without the confounding variables introduced by cutaneous burn or other pathology. OBJECTIVE: To develop a small animal model of pure SI-induced ALI and to use this model for eventual testing of novel therapeutics for ALI. METHODS: Rats were exposed to smoke using a custom-made smoke generator. Peripheral oxygen saturation (SpO2), heart rate, arterial blood gas, and chest X-ray (CXR) were measured before and after SI. Wet/dry weight (W/D) ratio, lung injury score and immunohistochemical staining of cleaved caspase 3 were performed on harvested lung tissues of healthy and SI animals. RESULTS: The current study demonstrates the induction of ALI in rats after SI as reflected by a significant, sustained decrease in SpO2 and the development of diffuse bilateral pulmonary infiltrates on CXR. Lung tissue of animals exposed to SI showed increased inflammation, oedema and apoptosis as reflected by the increase in W/D ratio, injury score and cleaved caspase 3 level of the harvested tissues compared with healthy animals. CONCLUSION: We have successfully developed a small animal model of pure SI-induced ALI. This model is offered to the scientific community as a reliable model of isolated pulmonary SI-induced injury without the confounding variables of cutaneous injury or other systemic pathology to be used for study of novel therapeutics or other investigation.

Perioperative considerations in nonagenarians.

OBJECTIVE: The nation's aging population presents novel perioperative challenges. Potential benefits of operative interventions must be scrutinized in relation to recoverable quality of life. The purpose of this study is to evaluate common risk calculators used for medical decision making in a nonagenarian patient population. METHODS: Retrospective medical record review was performed on patients 90 years or older who underwent operative interventions requiring anesthesia at a large academic medical center between January 1, 2013, and December 31, 2017. GraphPad 8.2.1 was used for statistical analysis. RESULTS: Significant differences were found when data were stratified by age for elective versus emergent cases (P value < .0001), ability to return to baseline function (P value  = .0062), and mortality (P value < .0001). Significant differences were found in emergent and elective cases, ability to return to baseline function, readmissions, and mortality (all P values < .0001) when stratified by American Society of Anesthesiologists score. Ability of patients to return to baseline functionality after intervention was influenced by their preintervention level of functionality (P value = .0008). American College of Surgeons and Portsmouth Physiologic and Operative Severity Score for Enumeration of Mortality and Morbidity risk calculators underestimated the need for rehabilitation and overestimated mortality for this population (all P values < .0001). CONCLUSION: Perioperative cares of the extreme geriatric population are complex and should be approached collaboratively. Rehabilitation and postoperative assistance resources should be assessed and used fully. Input from palliative care teams should be sought appropriately. End-of-life and escalation-of-care discussions should ideally be organized prior to emergent interventions. Frailty and risk calculators should be used and considered for formal implementation into the preoperative workflow.

Solid Organ Laceration in an Adolescent Soccer Player: A Case Report.

: Pediatric solid organ lacerations are a relatively uncommon but potentially dangerous injury that must be addressed urgently once recognized. Seen most often during recreational or team sports, they usually occur after a blunt or deceleration mechanism to the abdomen or flank. Depending on the severity of injury, solid organ laceration may not be immediately apparent clinically. This emphasizes the importance of sideline witnessing and evaluation, acting quickly once symptoms develop, and placing importance on safe sporting technique. In addition, management has changed over time to favor medical management for minor injuries, with laparotomy reserved for high-grade or hemodynamically unstable lacerations. Awareness of solid organ laceration in pediatric populations is more important than ever as they are beginning to appear in younger adolescents. Here we present a case of a 14-yr-old girl sustaining a grade IV liver laceration while playing contact team sports.

Isolated prehospital hypotension correlates with injury severity and outcomes in patients with trauma.

OBJECTIVE: Patients normotensive in the trauma bay despite documented prehospital hypotension may not be recognized as significantly injured. The purpose of this study was to determine whether isolated prehospital hypotension portends poor outcomes and correlates with injury severity. METHODS: Prospective cohort study conducted at a level 1 university trauma center. The lowest recorded prehospital systolic blood pressure (SBP) and the first recorded SBP on hospital arrival were used to divide patients into either the normotensive (NP) or hypotensive (HP) group. Patients who failed to achieve normotension on hospital arrival were excluded. Hypotension was defined as SBP≤110 mmHg. RESULTS: Compared to NP (n=206), HP (n=81) had lower Glasgow Coma Scores both prehospital (12.81±0.44 vs 14.38±0.13) and at hospital admission (12.78±0.47 vs 14.37±0.14). Injury Severity Score positively correlated with prehospital hypotension (HP 12.27±1.12 vs NP 9.22±0.49). Prehospital hypotension positively correlated with intensive care unit (ICU) admission (HP 56.79% vs NP 22.82%), ICU length of stay (LOS) (HP 3.23±0.71 vs NP 0.71±0.17), hospital LOS (HP 8.58±1.39 vs NP 4.86±0.33), ventilator days (HP 3.38±1.20 vs NP 0.27±0.08 days), and repeat hypotensive episodes during their hospital stay (HP 81.71% vs NP 38.16%). HP also required more packed red blood cells in the first 24 hours after admission (22% vs 6%). Significance was set at p<0.05. CONCLUSIONS: Isolated prehospital hypotension in patients in the trauma and emergency department correlates with increased injury severity and portends worse outcomes despite a normal blood pressure reading at admission. Prehospital hypotension must be given heavy consideration in triage, as these patients may be transiently hypotensive and appear less critical than their true status. LEVEL OF EVIDENCE: Level II, Prognostic study.

Deep venous thrombosis and venous thromboembolism prophylaxis.

"Venous thromboembolism (VTE) remains a significant risk for all surgical patients, despite validated guidelines. Development of VTE remains a high risk in hospitalized surgical patients, leading to complications in up to 30%. The stratification of patient risk factors and subsequent utilization of a validated prophylaxis and treatment regimen is, therefore, of utmost importance. Familiarity with the current guidelines and recommendations ultimately results in decreased morbidity, mortality, and health care costs. This article discusses the risk factors for developing VTE and management strategies based on the currently available guidelines."

Partial splenectomy for hereditary spherocytosis: a multi-institutional review.

BACKGROUND/PURPOSE: Partial splenectomy has emerged as a surgical option for selected children with hereditary spherocytosis, with the goal of reducing anemia while preserving splenic function. This multi-institutional study is the largest series to date examining outcomes data for partial splenectomy in patients with hereditary spherocytosis. METHODS: Data were collected retrospectively from 5 North American pediatric hospitals. Sixty-two children underwent partial splenectomy for hereditary spherocytosis between 1990 and 2008. RESULTS: At 1 year following partial splenectomy, mean hemoglobin significantly increased by 3.0 ± 1.4 g/dL (n = 52), reticulocyte count decreased by 6.6% ± 6.6% (n = 41), and bilirubin level decreased by 1.3 ± 0.9 mg/dL (n = 25). Patients with poor or transient hematologic response were found to have significantly more splenic regeneration postoperatively compared with patients with a durable clinical response (maximal spleen dimension, 9.0 ± 3.4 vs 6.3 ± 2.2 cm). Clinically significant recurrence of anemia or abdominal pain led to completion splenectomy in 4.84% of patients. No patients developed postsplenectomy sepsis. CONCLUSIONS: Our multi-institutional review indicates that partial splenectomy for hereditary spherocytosis leads to sustained and clinically significant improvement in hematologic profiles and clinical symptoms in most patients. Our data support partial splenectomy as an alternative for selected children with hereditary spherocytosis.

Castleman disease: surgical cure in pediatric patients.

Castleman disease is a rare disorder characterized by lymphoid hyperplasia which rarely manifests in children. We present 2 cases which highlight both histologic variants of this disease, and provide suggestions regarding workup and treatment with the goal of making practitioners aware of Castleman disease in the differential diagnosis of a child presenting with vague symptoms.