Wide-Field Fluorescein Angiography in Patients with Idiopathic Acute Anterior Uveitis.

PURPOSE: To elucidate whether wide-field fluorescein angiography (WFFA) can yield additional information in patients with newly diagnosed idiopathic acute anterior uveitis (AAU). METHODS: The WFFA was performed in patients with idiopathic AAU, and the findings were analyzed according to the scoring system by Angiography Scoring for Uveitis Nomenclature. RESULTS: Forty-four eyes of 30 patients (22 eyes of 13 patients in the pediatric group and 22 eyes of 17 patients in the adult group) were studied. The mean age was 12.41 ± 3.92 (range, 5-18) years in the pediatric group and 42.36 ± 32.07 (range, 24-68) years in the adult group. Thirteen eyes (59%) of pediatric patients and 12 eyes (54%) of adult patients showed some evidence of posterior segment activity on the WFFA (p = .764).     Systemic treatment was administered in 53.8% of the pediatric and 5.9% of adult patients, depending on the disease severity. CONCLUSION: Pediatric patients with idiopathic AAU may have subtle posterior segment manifestations more than adult patients, and posterior segment findings may affect the treatment preferences of physicians.

Case report: Catastrophic event: neonatal gastric perforation and complication of capillary leak syndrome.

Neonatal gastric perforation (NGP) is a rare, but life-threatening condition that can lead to serious conditions, such as capillary leak syndrome (CLS). Here, we present the case of a preterm male infant with NGP complicated by CLS after stomach repair. The patient was born at 33 2/7 weeks, weighed 1,770 g, and was diagnosed with respiratory distress syndrome. On the fourth day of life, the patient presented with distention and an unstable cardiovascular system. Routine blood tests revealed a white blood cell count of 2.4 × 109/L. Chest and abdominal radiography revealed a pneumoperitoneum, suggesting a gastrointestinal perforation. The patient was urgently transferred to a tertiary hospital for exploratory laparotomy, where a 2 cm diameter perforation was discovered in the stomach wall and subsequently repaired. Pathological findings indicated the absence of a muscular layer in the stomach wall. The patient unexpectedly developed CLS postoperatively, leading to multiorgan dysfunction and eventual death. The underlying pathological mechanism of NGP-induced CLS may be related to severe chemical peritonitis, sepsis, endothelial glycocalyx dysfunction, enhanced systemic inflammation, and translocation of the gut microbiota, causing endothelial hyperpermeability. Notablely, abdominal surgery itself can be a significant triggering factor for CLS occurrence. Complications of NGP and CLS are extremely dangerous. Investigating the mechanism by which NGP triggers CLS could potentially improve the prognosis. Conservative treatment for pneumoperitoneum secondary to gastric perforation may be a reasonable option, especially when the condition of the patient is unstable.

Establishment of a Rat Model of Capillary Leakage Syndrome Induced by Cardiopulmonary Resuscitation After Cardiac Arrest.

OBJECTIVE: Cardiopulmonary resuscitation (CPR) after cardiac arrest (CA) is one of the main causes of capillary leakage syndrome (CLS). This study aimed to establish a stable CLS model following the CA and cardiopulmonary resuscitation (CA-CPR) model in Sprague-Dawley (SD) rats. METHODS: We conducted a prospective, randomized, animal model study. All adult male SD rats were randomly divided into a normal group (group N), a sham operation group (group S), and a cardiopulmonary resuscitation group (group T). The SD rats of the three groups were all inserted with 24-G needles through their left femoral arteries and right femoral veins. In group S and group T, the endotracheal tube was intubated. In group T, CA induced by asphyxia (AACA) was caused by vecuronium bromide with the endotracheal tube obstructed for 8 min, and the rats were resuscitated with manual chest compression and mechanical ventilation. Preresuscitation and postresuscitation measurements, including basic vital signs (BVS), blood gas analysis (BG), routine complete blood count (CBC), wet-to-dry ratio of tissues (W/D), and the HE staining results after 6 h were evaluated. RESULTS: In group T, the success rate of the CA-CPR model was 60% (18/30), and CLS occurred in 26.6% (8/30) of the rats. There were no significant differences in the baseline characteristics, including BVS, BG, and CBC, among the three groups (P>0.05). Compared with pre-asphyxia, there were significant differences in BVS, CBC, and BG, including temperature, oxygen saturation (SpO2), mean arterial pressure (MAP), central venous pressure (CVP), white blood cell count (WBC), hemoglobin, hematocrit, pH, pCO2, pO2, SO2, lactate (Lac), base excess (BE), and Na+ (P<0.05) after the return of spontaneous circulation (ROSC) in group T. At 6 h after ROSC in group T and at 6 h after surgery in groups N and S, there were significant differences in temperature, heart rate (HR), respiratory rate (RR), SpO2, MAP, CVP, WBC, pH, pCO2, Na+, and K+ among the three groups (P<0.05). Compared with the other two groups, the rats in group T showed a significantly increased W/D weight ratio (P<0.05). The HE-stained sections showed consistent severe lesions in the lung, small intestine, and brain tissues of the rats at 6 h after ROSC following AACA. CONCLUSION: The CA-CPR model in SD rats induced by asphyxia could reproduce CLS with good stability and reproducibility.

The capillary-leakage syndrome caused by glyphosate poisoning: a case report.

Glyphosate is widely used in agriculture even though it can cause self-poisoning, inducing gastrointestinal disturbance, acute respiratory distress syndrome, arrhythmia, renal failure, and even death. Case presentation: The authors present a case of glyphosate poisoning in a patient who developed capillary-leak syndrome, severe metabolic acidosis, and shock. After treatment with hemoperfusion and continuous renal replacement therapy, the patient was extubated after 7 days and transferred out of the intensive care unit after 10 days. Clinical discussion: Severe glyphosate poisoning can lead to multiple organ failure and systemic capillary leak syndrome. Clinical manifestations of systemic capillary leak syndrome included hemoconcentration, increased hematocrit, hypoalbuminemia, interstitial fluid accumulation, and refractory hypotension. Substantial improvement of capillary leakage was observed only gradually after initiation of early continuous renal replacement therapy, plasma infusion, and application of ulinastatin. Conclusions: This case report highlights the life-threatening nature of glyphosate poisoning. Aggressive treatment and careful monitoring of complications are required, particularly in patients at risk of capillary leakage syndrome.

Rumpel-Leede Phenomenon Associated with Pneumatic Compression: A Case Report.

Rumpel-Leede phenomenon is a rarely reported condition with an unknown prevalence. It is characterized by the acute development of non-blanchable purpuric macules resulting from dermal capillary rupture caused by compressive forces. We report a case of Rumpel-Leede phenomenon in both feet following the application of pneumatic compression in a 49-year-old woman who underwent en bloc spondylectomy for a giant cell tumor of the spine. The condition appeared after the application of pneumatic compression on both legs for venous thromboembolism prophylaxis, and the lesions spontaneously resolved after discontinuation of compression. Currently, most cases are reported in patients with a history of diabetes mellitus, hypertension, or thrombocytopenia. We report a case of Rumpel-Leede phenomenon in a patient without underlying medical conditions. In our patient, capillary fragility combined with increased intracapillary pressure was hypothesized as the underlying mechanism.

Targeting Procalcitonin Protects Vascular Barrier Integrity.

Rationale: Capillary leakage frequently occurs during sepsis and after major surgery and is associated with microvascular dysfunction and adverse outcome. Procalcitonin is a well-established biomarker in inflammation without known impact on vascular integrity. Objectives: We determined how procalcitonin induces endothelial hyperpermeability and how targeting procalcitonin protects vascular barrier integrity. Methods: In a prospective observational clinical study, procalcitonin levels were assessed in 50 patients who underwent cardiac surgery and correlated to postoperative fluid and vasopressor requirements along with sublingual microvascular functionality. Effects of the procalcitonin signaling pathway on endothelial barrier and adherens junctional integrity were characterized in vitro and verified in mice. Inhibition of procalcitonin activation by dipeptidyl-peptidase 4 (DPP4) was evaluated in murine polymicrobial sepsis and clinically verified in cardiac surgery patients chronically taking the DPP4 inhibitor sitagliptin. Measurements and Main Results: Elevated postoperative procalcitonin levels identified patients with 2-fold increased fluid requirements (P < 0.01), 1.8-fold higher vasopressor demand (P < 0.05), and compromised microcirculation (reduction to 63.5 ± 2.8% of perfused vessels, P < 0.05). Procalcitonin induced 1.4-fold endothelial and 2.3-fold pulmonary capillary permeability (both Ps < 0.001) by destabilizing VE-cadherin. Procalcitonin effects were dependent on activation by DPP4, and targeting the procalcitonin receptor or DPP4 during sepsis-induced hyperprocalcitonemia reduced capillary leakage by 54 ± 10.1% and 60.4 ± 6.9% (both Ps < 0.01), respectively. Sitagliptin before cardiac surgery was associated with augmented microcirculation (74.1 ± 1.7% vs. 68.6 ± 1.9% perfused vessels in non-sitagliptin-medicated patients, P < 0.05) and with 2.3-fold decreased fluid (P < 0.05) and 1.8-fold reduced vasopressor demand postoperatively (P < 0.05). Conclusions: Targeting procalcitonin's action on the endothelium is a feasible means to preserve vascular integrity during systemic inflammation associated with hyperprocalcitonemia.

Regulation and Dysregulation of Endothelial Permeability during Systemic Inflammation.

Systemic inflammation can be triggered by infection, surgery, trauma or burns. During systemic inflammation, an overshooting immune response induces tissue damage resulting in organ dysfunction and mortality. Endothelial cells make up the inner lining of all blood vessels and are critically involved in maintaining organ integrity by regulating tissue perfusion. Permeability of the endothelial monolayer is strictly controlled and highly organ-specific, forming continuous, fenestrated and discontinuous capillaries that orchestrate the extravasation of fluids, proteins and solutes to maintain organ homeostasis. In the physiological state, the endothelial barrier is maintained by the glycocalyx, extracellular matrix and intercellular junctions including adherens and tight junctions. As endothelial cells are constantly sensing and responding to the extracellular environment, their activation by inflammatory stimuli promotes a loss of endothelial barrier function, which has been identified as a hallmark of systemic inflammation, leading to tissue edema formation and hypotension and thus, is a key contributor to lethal outcomes. In this review, we provide a comprehensive summary of the major players, such as the angiopoietin-Tie2 signaling axis, adrenomedullin and vascular endothelial (VE-) cadherin, that substantially contribute to the regulation and dysregulation of endothelial permeability during systemic inflammation and elucidate treatment strategies targeting the preservation of vascular integrity.

Capillary hyperpermeability syndrome: A fatal complication of acute leukaemia: Case report and review.

INTRODUCTION: The capillary hyperpermeability syndrome is a rare disease that should be suspected in the presence of recurrent generalized edema without obvious cause, which may be idiopathic or secondary. CASE PRESENTATION: In this case, we report a Clarkson syndrome secondary to an acute leukemia affecting a 4-year-old child admitted to the emergency room in respiratory and hemodynamic distress with a generalized oedematous syndrome and a bone marrow failure syndrome. Laboratory tests concluded that the patient was suffering from an acute lymphoblastic leukemia, hypoalbuminemia, pericardial effusion, and the absence of any other cause that is in favor of a capillary leak syndrome.In spite of the filling and the introduction of drugs, the cardio respiratory arrest could not be recovered and the child died 24h after his admission. DISCUSSION: It is a rare pathology described for the first time in 1960, generally secondary to a pathological state and more rarely idiopathic, to be evoked in front of clinical and biological parameters which are hypoalbuminemia, hemiconcentration and hypoperfusion, after having eliminated a sepsis in the first place.The treatment is based on the management of the acute phase by filling with crystalloids, drugs or even steroids, and as a preventive treatment of relapses immunoglobulins or theophylline are used. CONCLUSION: The evolution can be quickly fatal, that's why it is necessary to know how to evoke this syndrome in front of a similar clinical presentation.

Veno-venous-extracorporeal membrane oxygenation treatment for severe capillary leakage syndrome: A case report.

BACKGROUND: Capillary leak syndrome (CLS) is characterized by the leakage of large amounts of fluid and plasma proteins into the interstitial space, resulting in hypoalbuminemia, hypovolemic shock, elevated blood concentration, systemic progressive edema, and multiple serosal cavity effusion. Clinical syndromes such as cavity effusion pose a grave threat to the life and health of the patient. CASE SUMMARY: A 58-year-old female patient was admitted to the hospital after being in a coma for 6 h following accidental ingestion of a pesticide. She was treated with phencyclidine hydrochloride and pralidoxime iodide for detoxification, mechanical ventilation to maintain oxygen supply, continuous renal replacement therapy to maintain the internal environment, and hemoperfusion to promote the excretion of toxins. She also received a transfusion of red blood cells and massive fluid resuscitation. However, her blood pressure was not maintained. The patient was diagnosed with CLS due to pesticide poisoning. Oxygenation was difficult to maintain under full ventilator support; therefore, veno-venous-extracorporeal membrane oxygenation (VV-ECMO) treatment was given 13 h after admission. Her oxygenation level improved, but a large amount of ascites and pleural effusion soon became apparent. We continued drainage with an indwelling drainage tube, and the ECMO flow stabilized. The leakage gradually decreased, and ECMO was discontinued 3 d later. On the 6th day, the patient recovered from unconsciousness, but on gastroscopic evaluation, severe erosions were found in her entire stomach. With the family's consent, treatment was stopped, and the patient was discharged from the hospital on the 7th day. CONCLUSION: ECMO, liquid resuscitation and management, and improvement in plasma colloidal osmotic pressure, circulation, and tissue oxygen supply are crucial in treating CLS.

ABO and Rhesus Blood Groups in Acute Puumala Hantavirus Infection.

Puumala hantavirus (PUUV) causes hemorrhagic fever with renal syndrome. We aimed to evaluate whether ABO and rhesus blood groups associate with the susceptibility or the severity of PUUV infection. We analyzed blood groups in 289 adult patients treated in Tampere University hospital due to PUUV infection during the years 1982-2017. Patients' blood group distribution was compared to that of healthy, voluntary blood donors living in the Tampere University Hospital responsibility area (n = 21,833). The severity of PUUV infection, as judged by the severity of acute kidney injury (AKI), thrombocytopenia, inflammation, capillary leakage, and the length of hospital care, was analyzed across the groups. The ABO and rhesus blood group distributions did not differ between the patients and blood donors. Patients with non-O blood groups had lower systolic blood pressure compared to patients with blood group O, but there was no difference in other markers of capillary leakage or in the severity of AKI. Minor deviations in the number of platelets and leukocytes were detected between the O and non-O blood groups. To conclude, patients with blood group O may be less susceptible to hypotension, but otherwise blood groups have no major influences on disease susceptibility or severity during acute PUUV infection.

Flow-dependent regulation of endothelial Tie2 by GATA3 in vivo.

BACKGROUND: Reduced endothelial Tie2 expression occurs in diverse experimental models of critical illness, and experimental Tie2 suppression is sufficient to increase spontaneous vascular permeability. Looking for a common denominator among different critical illnesses that could drive the same Tie2 suppressive (thereby leak inducing) phenotype, we identified "circulatory shock" as a shared feature and postulated a flow-dependency of Tie2 gene expression in a GATA3 dependent manner. Here, we analyzed if this mechanism of flow-regulation of gene expression exists in vivo in the absence of inflammation. RESULTS: To experimentally mimic a shock-like situation, we developed a murine model of clonidine-induced hypotension by targeting a reduced mean arterial pressure (MAP) of approximately 50% over 4 h. We found that hypotension-induced reduction of flow in the absence of confounding disease factors (i.e., inflammation, injury, among others) is sufficient to suppress GATA3 and Tie2 transcription. Conditional endothelial-specific GATA3 knockdown (B6-Gata3tm1-Jfz VE-Cadherin(PAC)-cerERT2) led to baseline Tie2 suppression inducing spontaneous vascular leak. On the contrary, the transient overexpression of GATA3 in the pulmonary endothelium (jet-PEI plasmid delivery platform) was sufficient to increase Tie2 at baseline and completely block its hypotension-induced acute drop. On the functional level, the Tie2 protection by GATA3 overexpression abrogated the development of pulmonary capillary leakage. CONCLUSIONS: The data suggest that the GATA3-Tie2 signaling pathway might play a pivotal role in controlling vascular barrier function and that it is affected in diverse critical illnesses with shock as a consequence of a flow-regulated gene response. Targeting this novel mechanism might offer therapeutic opportunities to treat vascular leakage of diverse etiologies.

Gallbladder Wall Thickening associated with Dengue Shock Syndrome in a German traveller - no indication for surgical therapy - a case report.

BACKGROUND: With the increasing number of dengue virus infections imported into Germany, knowledge about the different phases of the disease and possible complications is essential for the treatment of patients. The virus is endemic in the tropics and subtropics and up to 2.5 billion people are at risk of infection. CASE PRESENTATION: Here we present a German traveller with dengue shock syndrome after returning from Thailand. After hospitalization the patient developed acute upper abdominal pain. The ultrasound findings were consistent with an acute acalculous cholecystitis, but were interpreted as dengue associated gallbladder wall thickening (GBWT). Therefore a surgical intervention was not indicated and would have been associated with an higher risk of complications in this situation. Under supportive care spontaneous regression of GBWT could be documented by sonography four days later as well as complete resolution of clinical symptoms. CONCLUSION: GBWT in dengue virus infection mimicking acute cholecystitis is a differential diagnosis one should take into consideration in travellers returning from endemic areas and should be managed conservatively because of an high risk of bleeding and increased mortality under surgical therapy.

The Clinical Presentation of Puumala Hantavirus Induced Hemorrhagic Fever with Renal Syndrome Is Related to Plasma Glucose Concentration.

Puumala hantavirus (PUUV) causes a hemorrhagic fever with renal syndrome characterized by thrombocytopenia, increased capillary leakage, and acute kidney injury (AKI). As glucosuria at hospital admission predicts the severity of PUUV infection, we explored how plasma glucose concentration associates with disease severity. Plasma glucose values were measured during hospital care in 185 patients with PUUV infection. They were divided into two groups according to maximum plasma glucose concentration: P-Gluc < 7.8 mmol/L (n = 134) and P-Gluc ≥ 7.8 mmol/L (n = 51). The determinants of disease severity were analyzed across groups. Patients with P-Gluc ≥7.8 mmol/L had higher hematocrit (0.46 vs. 0.43; p < 0.001) and lower plasma albumin concentration (24 vs. 29 g/L; p < 0.001) than patients with P-Gluc < 7.8 mmol/L. They presented with higher prevalence of pulmonary infiltrations and pleural effusion in chest radiograph, higher prevalence of shock and greater weight change during hospitalization. Patients with P-Gluc ≥ 7.8 mmol/L were characterized by lower platelet count (50 vs. 66 × 109/L; p = 0.001), more severe AKI (plasma creatinine 272 vs. 151 µmol/L; p = 0.001), and longer hospital treatment (8 vs. 6 days; p < 0.001) than patients with P-Gluc < 7.8 mmol/L. Plasma glucose level is associated with the severity of capillary leakage, thrombocytopenia, inflammation, and AKI in patients with acute PUUV infection.

Efficacy and safety of early target-controlled plasma volume replacement with a balanced gelatine solution versus a balanced electrolyte solution in patients with severe sepsis/septic shock: study protocol, design, and rationale of a prospective, randomized, controlled, double-blind, multicentric, international clinical trial : GENIUS-Gelatine use in ICU and sepsis.

BACKGROUND: Sepsis is associated with capillary leakage and vasodilatation and leads to hypotension and tissue hypoperfusion. Early plasma volume replacement is required to achieve haemodynamic stability (HDS) and maintain adequate tissue oxygenation. The right choice of fluids to be used for plasma volume replacement (colloid or crystalloid solutions) is still a matter of debate, and large trials investigating the use of colloid solutions containing gelatine are missing. This study aims to investigate the efficacy and safety of plasma volume replacement using either a combined gelatine-crystalloid regime (1:1 ratio) or a pure crystalloid regime. METHODS: This is a prospective, controlled, randomized, double-blind, international, multicentric phase IV study with two parallel groups that is planned to be conducted at European intensive care units (ICUs) in a population of patients with hypovolaemia in severe sepsis/septic shock. A total of 608 eligible patients will be randomly assigned to receive either a gelatine-crystalloid regime (Gelaspan® 4% and Sterofundin® ISO, B. Braun Melsungen AG, in a 1:1 ratio) or a pure crystalloid regime (Sterofundin® ISO) for plasma volume replacement. The primary outcome is defined as the time needed to achieve HDS. Plasma volume replacement will be target-controlled, i.e. fluids will only be administered to volume-responsive patients. Volume responsiveness will be assessed through passive leg raising or fluid challenges. The safety and efficacy of both regimens will be assessed daily for 28 days or until ICU discharge (whichever occurs first) as the secondary outcomes of this study. Follow-up visits/calls will be scheduled on day 28 and day 90. DISCUSSION: This study aims to generate evidence regarding which regimen-a gelatine-crystalloid regimen or a pure crystalloid regimen-is more effective in achieving HDS in critically ill patients with hypovolaemia. Study participants in both groups will benefit from the increased safety of target-controlled plasma volume replacement, which prevents fluid administration to already haemodynamically stable patients and reduces the risk of harmful fluid overload. TRIAL REGISTRATION: The European clinical trial database EudraCT 2015-000057-20 and the ClinicalTrials.gov Protocol Registration and Results System ClinicalTrials.gov NCT02715466 . Registered on 17 March 2016.

Micropulse laser in patients with refractory and treatment-naïve center-involved diabetic macular edema: short terms visual and anatomic outcomes.

PURPOSE: The purpose of the study is to describe visual and anatomic outcomes of 5774nm micropulse laser photocoagulation in eyes with either treatment-naïve or refractory diabetic macular edema (DME) at 3 months. METHODS: This was a prospective case series that recruited 23 consecutive patients (33 eyes) with center-involved DME that was either treatment-naïve or had not responded to prior treatment. Micropulse therapy was performed with the Easy Ret 577 (Quantel Medical, Cournon d'Auvergne, France) diode laser in a high-density manner in eyes with treatment-naïve or refractory DME. The primary outcome was the change of best-corrected visual acuity (BCVA; logMAR) at 1 and 3 months. Secondary outcomes were changes in the central macular thickness (CMT), thickness area, macular volume, and macular capillary leakage at 1 and 3 months. RESULTS: There were no significant changes in BCVA at 3 months, with mean ± standard deviation (SD) of -0.08 ± 0.01 (p = 0.228) and + 0.01 ± 0.01 (p = 0.969) for treatment-naïve and refractory groups, respectively. The change in CMT at 3 months was statistically but not clinically significant in the treatment-naïve group only (mean ± SD; -30 ± 130 µm; p = 0.011). The macular volume and area thickness change were not statistically significant (p = 0.173 and p = 0.148 for macular volume and area thickness, respectively) in the treatment-naïve group. There was no difference concerning the leakage area in both groups. No adverse events were reported. CONCLUSION: We concluded that micropulse 577nm laser therapy maintained the visual acuity and macular thickness at 3 months in both treatment-naïve and refractory DME.

Hypoalbuminemia in COVID-19: assessing the hypothesis for underlying pulmonary capillary leakage.

BACKGROUND: Since the first observations of patients with COVID-19, significant hypoalbuminaemia was detected. Its causes have not been investigated yet. OBJECTIVE: We hypothesized that pulmonary capillary leakage affects the severity of respiratory failure, causing a shift of fluids and proteins through the epithelial-endothelial barrier. METHODS: One hundred seventy-four COVID-19 patients with respiratory symptoms, 92 admitted to the intermediate medicine ward (IMW) and 82 to the intensive care unit (ICU) at Luigi Sacco Hospital in Milan, were studied. RESULTS: Baseline characteristics at admission were considered. Proteins, interleukin 8 (IL-8) and interleukin 10 (IL-10) in bronchoalveolar lavage fluid (BALF) were analysed in 26 ICU patients. In addition, ten autopsy ultrastructural lung studies were performed in patients with COVID-19 and compared with postmortem findings in a control group (bacterial pneumonia-ARDS and H1N1-ARDS). ICU patients had lower serum albumin than IMW patients [20 (18-23) vs 28 (24-33) g L-1 , P < 0.001]. Serum albumin was lower in more compromised groups (lower PaO2 -to-FiO2 ratio and worst chest X-ray findings) and was associated with 30 days of probability of survival. Protein concentration was correlated with IL-8 and IL-10 levels in BALF. Electron microscopy examinations of eight out of ten COVID-19 lung tissues showed loosening of junctional complexes, quantitatively more pronounced than in controls, and direct viral infection of type 2 pneumocytes and endothelial cells. CONCLUSION: Hypoalbuminaemia may serve as severity marker of epithelial-endothelial damage in patients with COVID-19. There are clues that pulmonary capillary leak syndrome plays a key role in the pathogenesis of COVID-19 and might be a potential therapeutic target.

C1 Inhibitor Administration Reduces Local Inflammation and Capillary Leakage, Without Affecting Long-term Wound Healing Parameters, in a Pig Burn Wound Model.

BACKGROUND: Burns induce a boost in local and systemic complement levels as well as immune cell infiltration in the burn wound, which may negatively affect wound healing. OBJECTIVE: In this study, the effects of long-term treatment with complement inhibitor C1 esterase inhibitor (C1inh) on post-burn inflammation and wound healing parameters were analyzed in time up to 60 days post-burn. METHODS: Burned pigs were treated either with or without C1inh up to 15 days post-burn. Burn wound biopsies and blood were collected at different time points up to 60 days post-burn. Thereafter, complement in blood as well as complement and immune cells in the wound, capillary leakage, necrosis, reepithelialization and wound contraction were quantified. RESULTS: No significant differences in complement C3 blood levels were observed at any time point between C1inh-treated and control pigs. In the wound, complement C4 levels were significantly lower in the C1inh group than in controls at day 3-6 and 21-30 post-burn. Similarly, C3 levels, neutrophil and macrophage infiltration in the wound were, although not statistically significant, reduced in C1inh-treated pigs at day 9-14 post-burn. No differences in lymphocyte infiltration in the wound were found between C1inh and control pigs. C1inh-treated pigs also showed reduced capillary leakage. Despite these effects, no significant differences in the long-term wound healing parameters necrosis, reepithelialization and wound contraction were observed between C1inh and control pigs. CONCLUSION: In pigs, 15 days of C1inh treatment after burn, leads to a reduction in local inflammation and capillary leakage in the burn wound without affecting long-term wound healing parameters.

Vascular Decoupling in Septic Shock: The Combined Role of Autonomic Nervous System, Arterial Stiffness, and Peripheral Vascular Tone.

BACKGROUND: Acute inflammation and sepsis are known to induce changes in vascular properties, leading to increased arterial stiffness; at the same time, the autonomic nervous system (ANS) also affects vascular properties by modulating the arterial smooth muscle tone, and it is widely reported that sepsis and septic shock severely impair ANS activity. Currently, clinical guidelines are mainly concerned to resuscitate septic shock patients from hypotension, hypovolemia, and hypoperfusion; however, if the current resuscitation maneuvers have a beneficial effect also on vascular properties and autonomic functionality is still unclear. The objective of this work is to assess the effects of standard resuscitation at vascular level and to verify if there is any association between alterations in vascular properties and ANS activity. METHODS: Six pigs underwent a protocol of polymicrobial septic shock and resuscitation (fluids and noradrenaline). The arterial blood pressure (ABP) waveform was recorded in the central aorta and in the peripheral radial and femoral artery. The characteristic arterial time constant was computed at the three arterial sites based on the two-element Windkessel model, to characterize the overall arterial vascular tree. Moreover, independent estimates of total arterial compliance (AC) and total peripheral resistance (TPR) were performed. Baroreflex sensitivity (BRS), low frequency (LF, 0.04-0.15 Hz) spectral power of diastolic blood pressure, and indices of heart rate variability (HRV) were computed to assess ANS functionality. RESULTS: Septic shock induced a severe vascular disarray, decoupling the usual pressure wave propagation from central to peripheral sites; this phenomenon appeared as an inversion of the physiological pulse pressure (PP) amplification, with a higher PP in the central aorta than in the peripheral arteries. The time constant was decreased, together with AC and TPR. ANS dysfunction was described by a reduced BRS, decreased LF power, and suppressed HRV. This compromised condition was not resolved by administration of fluids and noradrenaline. Thus, a persistent vascular and autonomic dysfunction were reported also in the resuscitated animals, and they were found to be significantly correlated. CONCLUSION: Measures of vascular function and ANS activity could add information to standard hemodynamic and clinical markers, and the current resuscitation strategies could benefit from the adjunction of these additional functional indices.

Engraftment Syndrome and Acute Graft-versus-Host Disease: A Meta-Analysis.

Engraftment syndrome (ES) has been associated with the surge of neutrophils and cytokines, which is similar to the presumed underlying pathophysiology behind acute graft-versus-host disease (aGVHD). However, there has been no meta-analysis to evaluate the association; therefore, the team attempted to verify an association between ES and aGVHD through meta-analysis. The team searched for titles of articles in MEDLINE (PubMed), the Cochrane Library, and the EMBASE database up until December 2018 that evaluated the association between ES and aGVHD and conducted a random effect meta-analysis of 8 studies involving a total of 1,945 participants to report the pooled odds ratio (OR) for association of ES and aGVHD. The team found a significantly increased odds of developing aGVHD in patients with ES with the pooled OR of 2.76 (95% confidence interval [CI]: 1.64-4.63) and an I2= 64.5%. In conclusion, patients with ES have significantly higher odds of developing aGVHD compared to patients without ES.

Endothelial glycocalyx shedding in patients with burns.

Shedding of syndecan-1 from the endothelial glycocalyx layer (EGL), referred to as endotheliopathy of trauma (EoT), is associated with poorer outcomes. This study aims to determine if EoT is also present in the burn population. We enrolled 458 burn and non-burn trauma patients at a Level 1 trauma center and defined EoT by a syndecan-1 level of ≥40 ng/mL. Sixty-eight of the enrolled patients had burns with a median TBSA of 19%, with 27.9% also suffering inhalational injury (II). Mortality was similar between the burn and non-burn group, also for patients with EoT. The incidence of II was significantly greater in the EoT+ burn group compared to the EoT- group (p = 0.038). Patients with II received significantly larger amounts of i.v. fluids (p = 0.001). The incidence of EoT was significantly different between the II-groups, as was mortality (pEoT = 0.038, pmortality < 0.001). EoT is attributed to the shock rather than the mechanism of trauma and may in burns be associated to II rather than TBSA. Patients with burns and II had worse outcomes and higher mortality compared to patients with burns alone. Burn injury induces EGL shedding similar to that in non-burn patients with EoT, and results in similar higher rate of mortality.