INTRACOLON COOLING INCREASES SURVIVAL RATE IN THE RAT MODEL OF LETHAL HEMORRHAGE.

ABSTRACT: Background: The objective of this study was to investigate whether transrectal intracolon (TRIC) cooling can prolong the survival duration in a rat hemorrhagic shock (HS) model. Methods: A lethal HS was induced by bleeding 47% of the total blood volume. A TRIC device was placed into the colon to maintain the intracolon temperature either at 37°C (TRIC37) or at 10°C (TRIC10) post-HS. In the surface cooling (SC) rats, the body temperatures were maintained at the same level as the esophageal temperature of the TRIC10 rats. A separated group of TRIC10 rats were resuscitated (Res) at 90 min post-HS. A total of six groups were as follows: (i) Sham TRIC37 (n = 5), (ii) Sham TRIC10 (n = 5), (iii) HS TRIC37 (n = 5), (iv) HS TRIC10 (n = 6), (v) HS SC (n = 6), and (vi) HS TRIC10 + Res (n = 6). Results: An average post-HS survival time was 18.4 ± 9.4 min in HS TRIC37 and 82 ± 27.82 min in the HS SC group. In striking contrast, the HS TRIC10 group exhibited an average survival time of 150.2 ± 66.43 min. The post-HS blood potassium level rose significantly in the HS TRIC37 and HS SC, whereas it remained unchanged in the TRIC10 groups. Post-HS intestinal damage occurred in HS TRIC37 and HS SC groups but virtually absent in HS TRIC10 groups. After resuscitation at 90 min post-HS, all HS TRIC10 rats were fully recovered from the lethal HS. Conclusions: TRIC10 reversed the high blood potassium level, prevented the intestinal damage, and prolonged the survival duration by sixfold relative to normothermia and by twofold compared with SC post-HS. All TRIC10 rats were successfully resuscitated at 90 min post-HS.

Assessing prescriber adherence with Global Initiative for Asthma (GINA) guideline-recommended reliever therapy.

In 2019, a landmark change was made to the Global Initiative for Asthma (GINA) guidelines in which an as-needed low-dose inhaled corticosteroid (ICS)-formoterol inhaler was updated to be the preferred reliever therapy for all asthma patients. Use of short-acting beta-agonist monotherapy is no longer recommended. The purpose of this study was to assess provider adherence with the GINA guidelines in regards to reliever therapy. This was a retrospective cohort study of patients presenting with an acute asthma exacerbation from January to May of 2020 and 2021. The primary objective of this study was to quantify provider adherence with the GINA guidelines in terms of reliever therapy. Preferred reliever therapy was defined as use of an as-needed low-dose ICS-formoterol combination inhaler. Alternative reliever therapy was defined as use of a SABA inhaler with ICS-containing controller therapy. Secondary objectives included the number of patients discharged on any form of corticosteroid and the number of patients who may have been ideal candidates for transition to preferred reliever therapy. A total of 127 patients were included in the analyses. Upon hospital discharge, three patients (2.4%) received preferred reliever therapy and 97 (76.4%) received alternative reliever therapy. Rates of recommended reliever therapy prescription increased from 55 to 79% upon hospital discharge (p < 0.001). Prescription of GINA guideline-recommended reliever therapy was 79% within the patient population evaluated; however, rates significantly improved following hospitalization for asthma exacerbation. Additional studies that assess barriers to guideline adherence may be recommended.

Cathepsin B knockout confers significant brain protection in the mouse model of stroke.

BACKGROUND: Significant advances have been made in our understanding of the endolysosomal cycle. Disruption of this cycle leads to cell death. The objective of this study aims to investigate the role of disrupted endolysosomal cycle in brain ischemia-reperfusion injury. METHODS: A total of 57 mice were randomly assigned into four experimental groups: (i) wildtype (wt) sham control; (ii) wt middle cerebral artery occlusion (MCAO); (iii) cathepsin B (CTSB) knockout (KO) sham control; and (iv) CTSB KO MCAO. Mice were subjected either to 0 min (sham) or 40 min of MCAO, followed by reperfusion for 1 or 7 days. Physical and behavioral examinations were conducted in the 7-day reperfusion group for 7 consecutive days after MCAO. Confocal microscopy was used to assess the levels, redistributions, and co-localizations of key endolysosomal cycle-related proteins. Histopathology was examined by light microscopy. RESULTS: Confocal microscopy revealed a significant accumulation of CTSB in post-ischemic penumbral neurons relative to those in the sham group. In addition, N-ethylmaleimide sensitive factor ATPase (NSF) was irreversibly depleted in these neurons. Furthermore, CTSB-immunostained structures were enlarged and diffusely distributed in both the cytoplasm and extracellular space, indicating the release of CTSB from post-ischemic neurons. Compared to wt mice, CTSB KO mice showed a significant decrease in hippocampal injury area, a significant increase in the number of survival neurons in the striatal core area, and a significant improvement in physical and functional performance in post-MCAO mice. CONCLUSION: Brain ischemia leads to a cascade of events leading to inactivation of NSF, disruption of the endolysosomal cycle, endolysosomal structural buildup and damage, and the release of CTSB, eventually resulting in brain ischemia reperfusion injury. CTSB KO in mice protected the brain from ischemia-reperfusion injury.

Pressure-Dependent Pneumothorax and Air Leak: Physiology and Clinical Implications.

Pressure-dependent pneumothorax is a common clinical event, often occurring after pleural drainage in patients with visceral pleural restriction, partial lung resection, or lobar atelectasis from bronchoscopic lung volume reduction or an endobronchial obstruction. This type of pneumothorax and air leak is clinically inconsequential. Failure to appreciate the benign nature of such air leaks may result in unnecessary pleural procedures or prolonged hospital stay. This review suggests that identification of pressure-dependent pneumothorax is clinically important because the air leak that results is not related to a lung injury that requires repair but rather to a physiological consequence of a pressure gradient. A pressure-dependent pneumothorax occurs during pleural drainage in patients with lung-thoracic cavity shape/size mismatch. It is caused by an air leak related to a pressure gradient between the subpleural lung parenchyma and the pleural space. Pressure-dependent pneumothorax and air leak do not need any further pleural interventions.

Diagnosis of non-expandable lung using thoracic ultrasound.

Non-expandable lung (NEL) commonly occurs secondary to chronic pleural processes, including pleural effusions, endobronchial obstruction, atelectasis, or chronic pleural inflammatory processes. Patients with NEL frequently undergo unnecessary procedures (e.g., thoracentesis), resulting in pneumothorax and discomfort (usually chest pain). Identifying a chronic process and likely development of NEL may prevent this. Diagnostic modalities currently used in practice include pleural manometry and ultrasonography. This case report demonstrates that blunting of transmitted cardiac impulse on M-Mode of ultrasonography predicts the presence of NEL.

In vivo molecular imaging stratifies rats with different susceptibilities to hyperoxic acute lung injury.

99mTc-hexamethylpropyleneamine oxime (HMPAO) and 99mTc-duramycin in vivo imaging detects pulmonary oxidative stress and cell death, respectively, in rats exposed to >95% O2 (hyperoxia) as a model of acute respiratory distress syndrome (ARDS). Preexposure to hyperoxia for 48 h followed by 24 h in room air (H-T) is protective against hyperoxia-induced lung injury. This study's objective was to determine the ability of 99mTc-HMPAO and 99mTc-duramycin to track this protection and to elucidate underlying mechanisms. Rats were exposed to normoxia, hyperoxia for 60 h, H-T, or H-T followed by 60 h of hyperoxia (H-T + 60). Imaging was performed 20 min after intravenous injection of either 99mTc-HMPAO or 99mTc-duramycin. 99mTc-HMPAO and 99mTc-duramycin lung uptake was 200% and 167% greater (P < 0.01) in hyperoxia compared with normoxia rats, respectively. On the other hand, uptake of 99mTc-HMPAO in H-T + 60 was 24% greater (P < 0.01) than in H-T rats, but 99mTc-duramycin uptake was not significantly different (P = 0.09). Lung wet-to-dry weight ratio, pleural effusion, endothelial filtration coefficient, and histological indices all showed evidence of protection and paralleled imaging results. Additional results indicate higher mitochondrial complex IV activity in H-T versus normoxia rats, suggesting that mitochondria of H-T lungs may be more tolerant of oxidative stress. A pattern of increasing lung uptake of 99mTc-HMPAO and 99mTc-duramycin correlates with advancing oxidative stress and cell death and worsening injury, whereas stable or decreasing 99mTc-HMPAO and stable 99mTc-duramycin reflects hyperoxia tolerance, suggesting the potential utility of molecular imaging for identifying at-risk hosts that are more or less susceptible to progressing to ARDS.

Pressure-dependent persistent air leak in a patient with secondary spontaneous pneumothorax.

An air leak lasting more than 5-7 days (persistent air leak, PAL) can complicate up to 40% of patients with secondary spontaneous pneumothorax. Chronic obstructive pulmonary disease is the most common cause of secondary spontaneous pneumothorax, and early surgical intervention has been recommended for patients with PAL. Bullectomy or blebectomy with concomitant mechanical pleurodesis by medical thoracoscopy or video assisted thoracoscopic surgery is considered definitive therapy. Unfortunately, the perioperative course following lung resection can also be complicated by air leaks leading to worse clinical outcomes. Post lung resection air leak can be pressure independent or pressure dependent (also known as drainage-related air leak). The distinction between these two entities is crucial as the management varies drastically. Pleural manometry may play an important role in the early diagnosis of pressure-dependent PAL preventing further unnecessary surgical procedures from being performed.

Human Pulmonary Dirofilariasis: A Review for the Clinicians.

Human pulmonary dirofilariasis (HPD) is a rare zoonotic disease caused by Dirofilaria immitis, the nematode responsible for canine cardiopulmonary dirofilariasis (dog heartworm). The incidence of HPD is on the rise throughout the world due to increased awareness and factors affecting the vector (mosquito). Humans are accidental hosts for D. immitis. Most patients are asymptomatic and present with an incidental pulmonary nodule that mimics primary or metastatic pulmonary malignancy. Some patients suffer from pulmonary and systemic symptoms in the acute phase of pneumonitis caused by pulmonary arterial occlusion by the preadult worms resulting in pulmonary infarction and intense inflammation. These patients may have ill-defined pulmonary infiltrate on chest radiology. Pulmonary nodules represent the end result of initial pneumonitis. There are no specific clinical, laboratory, or radiologic findings that differentiate HPD from other causes of a pulmonary nodule. Although serologic tests exist, they are usually not commercially available. The majority of patients are diagnosed by histopathologic identification of the decomposing worm following surgical resection of the lesion.

Association between Drainage-Dependent Prolonged Air Leak after Partial Lung Resection and Clinical Outcomes: A Prospective Cohort Study.

Rationale: Prolonged air leak (PAL) after partial lung resection can occur owing to surgical complications or in the presence of residual thoracic space. The former type results in drainage-independent PAL (DIPAL), whereas the latter type results in drainage-dependent PAL (DDPAL). DDPAL is described after thoracentesis in patients with nonexpandable lung, where the thoracostomy tube can be discontinued safely despite an ongoing air leak. This distinction is clinically relevant, as in the presence of DDPAL, tube thoracostomy can be safely discontinued without the need for further interventions. Objectives: To determine the frequency and clinical relevance of DDAPL and DIPAL in patients with PAL after partial lung resection. Methods: We prospectively identified consecutive patients with PAL after partial lung resection. Pleural manometry was performed 3-5 days after surgery. Pleural pressure was measured for 20 minutes after clamping the thoracostomy tube. DDPAL was diagnosed if the end-expiratory pleural pressure remained stable after plateauing in the absence of respiratory symptoms. Results: Of 225 patients who underwent lung resection, we identified 22 (10%) who had PAL. Twenty patients had adequate pleural manometry readings. The majority, 16/20 (80%), had DDPAL and had lower median hospital length of stay than those with DIPAL (6.9 vs. 11 days; P = 0.02). All patients with DIPAL required reexploration surgery, whereas only one patient with DDPAL underwent reexploration surgery. Conclusions: Most PALs after partial lung resection are DDPAL. Patients with DDPAL have lower hospital length of stay and less need for reexploration surgery than those with DIPAL.

Food Coma: Hyperammonemic Encephalopathy From Refeeding Syndrome.

Hyperammonemic encephalopathy (HAE) from extrahepatic causes is increasingly being recognized. Refeeding syndrome is characterized by severe fluid and electrolyte shifts following the reintroduction of nutrition. We describe the case of a 67-year-old man with bilateral maxillary sinus squamous cell carcinoma on nivolumab who became comatose after initiation of enteral feeding. Initial workup was notable for severe hypophosphatemia (<1 mg/dL) and markedly elevated ammonia (226 µmol/L). Neuroimaging was unrevealing. Correction of hypophosphatemia did not improve mental status. Ammonia levels briefly decreased while holding enteral feeding but worsened again on resumption. High-volume continuous renal replacement therapy was recommended but deferred in accordance with family wishes. We hypothesize that HAE may have been precipitated by a combination of refeeding-induced high nitrogen burden and limited detoxification via the urea cycle and extrahepatic pathways in the setting of severe protein-energy malnutrition and underlying malignancy. Nivolumab could have contributed as well.

Interruption of Endolysosomal Trafficking After Focal Brain Ischemia.

A typical neuron consists of a soma, a single axon with numerous nerve terminals, and multiple dendritic trunks with numerous branches. Each of the 100 billion neurons in the brain has on average 7,000 synaptic connections to other neurons. The neuronal endolysosomal compartments for the degradation of axonal and dendritic waste are located in the soma region. That means that all autophagosomal and endosomal cargos from 7,000 synaptic connections must be transported to the soma region for degradation. For that reason, neuronal endolysosomal degradation is an extraordinarily demanding and dynamic event, and thus is highly susceptible to many pathological conditions. Dysfunction in the endolysosomal trafficking pathways occurs in virtually all neurodegenerative diseases. Most lysosomal storage disorders (LSDs) with defects in the endolysosomal system preferentially affect the central nervous system (CNS). Recently, significant progress has been made in understanding the role that the endolysosomal trafficking pathways play after brain ischemia. Brain ischemia damages the membrane fusion machinery co-operated by N-ethylmaleimide sensitive factor (NSF), soluble NSF attachment protein (SNAP), and soluble NSF attachment protein receptors (SNAREs), thus interrupting the membrane-to-membrane fusion between the late endosome and terminal lysosome. This interruption obstructs all incoming traffic. Consequently, both the size and number of endolysosomal structures, autophagosomes, early endosomes, and intra-neuronal protein aggregates are increased extensively in post-ischemic neurons. This cascade of events eventually damages the endolysosomal structures to release hydrolases leading to ischemic brain injury. Gene knockout and selective inhibition of key endolysosomal cathepsins protects the brain from ischemic injury. This review aims to provide an update of the current knowledge, future research directions, and the clinical implications regarding the critical role of the neuronal endolysosomal trafficking pathways in ischemic brain injury.

Management of complex pleural disease in the critically ill patient.

Disorders of the pleural space are quite common in the critically ill patient. They are generally associated with the underlying illness. It is sometimes difficult to assess for pleural space disorders in the ICU given the instability of some patients. Although the portable chest X-ray remains the primary modality of diagnosis for pleural disorders in the ICU. It can be nonspecific and may miss subtle findings. Ultrasound has become a useful tool to the bedside clinician to aid in diagnosis and management of pleural disease. The majority of pleural space disorders resolve as the patient's illness improves. There remain a few pleural processes that need specific therapies. While uncomplicated parapneumonic effusions do not have their own treatments. Those that progress to become a complex infected pleural space can have its individual complexity in therapy. Chest tube drainage remains the cornerstone in therapy. The use of intrapleural fibrinolytics has decreased the need for surgical referral. A large hemothorax or pneumothorax in patients admitted to the ICU represent medical emergencies and require emergent action. In this review we focus on the management of commonly encountered complex pleural space disorders in critically ill patients such as complicated pleural space infections, hemothoraces and pneumothoraces.

Comparing the outcomes of intrapleural fibrinolytic and DNase therapy versus intrapleural fibrinolytic or DNase therapy: A systematic review and meta-analysis.

BACKGROUND: Multiple studies describing the benefits of intrapleural fibrinolytic over placebo and DNase therapy have been published, but few have been published on intrapleural fibrinolytic and DNase therapy. OBJECTIVE: Our meta-analysis aims to compare the outcomes of surgical intervention, mortality, and hospital length of stay between intrapleural fibrinolytic and DNase therapy with either intrapleural fibrinolytic or DNase therapy alone in patients with pleural space infections. METHODS: We searched Pubmed, EMBASE, Web of Science, and Cochrane library databases for observational studies and randomized controlled trials (RCTs) containing comparative data for hospitalized adults and children with pleural infections receiving intrapleural therapy of fibrinolytic and DNase versus those receiving intrapleural fibrinolytic or DNase alone. Meta-analysis was performed using the Review Manager software, and heterogeneity was tested using I2 statistics. RESULTS: A total of 2 cohorts and 2 RCTs involving 362 adult and children was included. There was significant reduction in surgical intervention requirement among patients who received intrapleural fibrinolytic and DNase (OR 0.30; 95% CI 0.11-0.83; I2 = 31%; P = 0.02) than those receiving either intrapleural fibrinolytic or DNase alone. No difference was observed for mortality (OR 0.72; 95% CI 0.31-1.71; I2 = 0%; P = 0.46) and complication rates (OR 3.09; 95% CI 0.75-12,74; I2 = 54%; P = 0.12). The hospital length of stay (mean 13.70 vs. 16.67 days; P = 0.19) and duration of chest tube drainage (mean 6.47 vs. 6.30 days; P = 0.58) was similar between the two groups. CONCLUSION: Combination of intrapleural fibrinolytic and DNase, compared to single-agent intrapleural therapy alone, is associated with a lesser need for surgical interventions. However, no difference was found in mortality, hospital length of stay, and chest tube drainage duration.

Interruption of endolysosomal trafficking leads to stroke brain injury.

BACKGROUND AND PURPOSE: Dysfunction of the endolysosomal system can cause cell death. A key molecule for controlling the endolysosomal trafficking activities is the N-ethylmaleimide-sensitive factor (NSF) ATPase. This study investigates the cascades of NSF ATPase inactivation events, endolysosomal damage, cathepsin release, and neuronal death after focal brain ischemia. METHODS: A total of 62 rats were used in this study. They were subjected to sham surgery or 2 h of focal brain ischemia followed by 1, 4, and 24 h of reperfusion. Confocal microscopy and Western blot analysis were utilized to analyze the levels, redistribution, and co-localization of key proteins of the Golgi apparatus, late endosomes, endolysosomes, and lysosomes. Light and electron microscopy were used to examine the histopathology, protein aggregation, and endolysosomal ultrastructures. RESULTS: Two hours of focal brain ischemia in rats led to acute neuronal death at the striatal core in 4 h and a slower type of neuronal death in the neocortical area during 1-24 h reperfusion periods. Confocal microscopy showed that NSF immunoreactivity was irreversibly and selectively depleted from most, if not all, post-ischemic penumbral neurons. Western blot analysis further demonstrated that NSF depletion from brain sections was due to its deposition into dense inactive aggregates that could not be recognized by the NSF antibody. Commitantly, the Golgi apparatus was completely fragmented and cathepsin B (CTSB)-containing endolysosomal structures, as well as p62/SQSTM1- and EEA1-immunopositive structures were massively accumulated in the post-ischemic penumbral neurons. Ultimately, CTSB was released into the cytoplasm and extracellular space, causing stroke brain injury. CONCLUSION: Stroke Inactivates NSF, resulting in disruption of the reforming of functional endolysosomal compartments, blockade of the endocytic and autophagic pathways, a large scale of CTSB release into the cytoplasm and extracellular space, and stroke brain injury in the rat model.

Focal intra-colon cooling reduces organ injury and systemic inflammation after REBOA management of lethal hemorrhage in rats.

Resuscitative endovascular balloon occlusion of the aorta (REBOA) is a lifesaving maneuver for the management of lethal torso hemorrhage. However, its prolonged use leads to distal organ ischemia-reperfusion injury (IRI) and systemic inflammatory response syndrome (SIRS). The objective of this study is to investigate the blood-based biomarkers of IRI and SIRS and the efficacy of direct intestinal cooling in the prevention of IRI and SIRS. A rat lethal hemorrhage model was produced by bleeding 50% of the total blood volume. A balloon catheter was inserted into the aorta for the implementation of REBOA. A novel TransRectal Intra-Colon (TRIC) device was placed in the descending colon and activated from 10 min after the bleeding to maintain the intra-colon temperature at 37 °C (TRIC37°C group) or 12 °C (TRIC12°C group) for 270 min. The upper body temperature was maintained at as close to 37 °C as possible in both groups. Blood samples were collected before hemorrhage and after REBOA. The organ injury biomarkers and inflammatory cytokines were evaluated by ELISA method. Blood based organ injury biomarkers (endotoxin, creatinine, AST, FABP1/L-FABP, cardiac troponin I, and FABP2/I-FABP) were all drastically increased in TRIC37°C group after REBOA. TRIC12°C significantly downregulated these increased organ injury biomarkers. Plasma levels of pro-inflammatory cytokines TNF-α, IL-1b, and IL-17F were also drastically increased in TRIC37°C group after REBOA. TRIC12°C significantly downregulated the pro-inflammatory cytokines. In contrast, TRIC12°C significantly upregulated the levels of anti-inflammatory cytokines IL-4 and IL-10 after REBOA. Amazingly, the mortality rate was 100% in TRIC37°C group whereas 0% in TRIC12°C group after REBOA. Directly cooling the intestine offered exceptional protection of the abdominal organs from IRI and SIRS, switched from a harmful pro-inflammatory to a reparative anti-inflammatory response, and mitigated mortality in the rat model of REBOA management of lethal hemorrhage.

The incidence, clinical characteristics, and outcomes of pneumothorax in hospitalized COVID-19 patients: A systematic review.

BACKGROUND: Pneumothorax has been frequently described as a complication of COVID-19 infections. OBJECTIVE: In this systematic review, we describe the incidence, clinical characteristics, and outcomes of COVID-19-related pneumothorax. METHODS: Studies were identified through MEDLINE, Pubmed, and Google Scholar databases using keywords of "COVID-19," "SARS-CoV-2," "pneumothorax," "pneumomediastinum," and "barotrauma" from January 1st, 2020 to January 30th, 2021. RESULTS: Among the nine observational studies, the incidence of pneumothorax is low at 0.3% in hospitalized COVID-19 patients. However, the incidence of pneumothorax increases to 12.8-23.8% in those requiring invasive mechanical ventilation (IMV) with a high mortality rate up to 100%. COVID-19-related pneumothorax tends to be unilateral and right-sided. Age, pre-existing lung diseases, and active smoking status are not shown to be risk factors. The time to pneumothorax diagnosis is around 9.0-19.6 days from admission and 5.4 days after IMV initiation. COVID-19-related pneumothoraces are associated with prolonged hospitalization, increased likelihood of ICU admission and death, especially among the elderly. CONCLUSION: COVID-19-related pneumothorax likely signify greater disease severity. With the high variability of COVID-19-related pneumothorax incidence described, a well-designed study is required to better assess the significance of COVID-19-related pneumothorax.

Pneumothorax in critically ill patients with COVID-19 infection: Incidence, clinical characteristics and outcomes in a case control multicenter study.

BACKGROUND: The clinical features and outcomes of mechanically ventilated patients with COVID-19 infection who develop a pneumothorax has not been rigorously described or compared to those who do not develop a pneumothorax. PURPOSE: To determine the incidence, clinical characteristics, and outcomes of critically ill patients with COVID-19 infection who developed pneumothorax. In addition, we compared the clinical characteristics and outcomes of mechanically ventilated patients who developed a pneumothorax with those who did not develop a pneumothorax. METHODS: This study was a multicenter retrospective analysis of all adult critically ill patients with COVID-19 infection who were admitted to intensive care units in 4 tertiary care centers in the United States. RESULTS: A total of 842 critically ill patients with COVID-19 infection were analyzed, out of which 594 (71%) were mechanically ventilated. The overall incidence of pneumothorax was 85/842 (10%), and 80/594 (13%) in those who were mechanically ventilated. As compared to mechanically ventilated patients in the non-pneumothorax group, mechanically ventilated patients in the pneumothorax group had worse respiratory parameters at the time of intubation (mean PaO2:FiO2 ratio 105 vs 150, P<0.001 and static respiratory system compliance: 30ml/cmH2O vs 39ml/cmH2O, P = 0.01) and significantly higher in-hospital mortality (63% vs 49%, P = 0.04). CONCLUSION: The overall incidence of pneumothorax in mechanically ventilated patients with COVID-19 infection was 13%. Mechanically ventilated patients with COVID-19 infection who developed pneumothorax had worse gas exchange and respiratory mechanics at the time of intubation and had a higher mortality compared to those who did not develop pneumothorax.