Prevention of peri-interventional hypothermia during endoscopic retrograde cholangiopancreatography using a forced-air heating system.

Background and study aims Perioperative hypothermia is associated with significant complications and can be prevented with forced-air heating systems (FAHS). Whether hypothermia occurs during prolonged endoscopic sedation is unclear and prevention measures are not addressed in endoscopic sedation guidelines. We hypothesized that hypothermia also occurs in a significant proportion of patients undergoing endoscopic interventions associated with longer sedation times such as endoscopic retrograde cholangiopancreaticography (ERCP), and that FAHS may prevent it. Patients and methods In this observational study, each patient received two consecutive ERCPs, the first ERCP following current standard of care without FAHS (SOC group) and a consecutive ERCP with FAHS (FAHS group). The primary endpoint was maximum body temperature difference during sedation. Results Twenty-four patients were included. Median (interquartile range) maximum body temperature difference was -0.9°C (-1.2; -0.4) in the SOC and -0.1°C (-0.2; 0) in the FAHS group ( P < 0.001). Median body temperature was lower in the SOC compared with the FAHS group after 20, 30, 40, and 50 minutes of sedation. A reduction in body temperature of > 1°C ( P < 0.001) and a reduction below 36°C ( P = 0.01) occurred more often in the SOC than in the FAHS group. FAHS was independently associated with reduced risk of hypothermia ( P = 0.006). More patients experienced freezing in the SOC group ( P = 0.004). Hemodynmaic and respiratory stability were comparable in both groups. Conclusions Hypothermia occurred in the majority of patients undergoing prolonged endoscopic sedation without active temperature control. FAHS was associated with higher temperature stability during sedation and better patient comfort.

Concordance of emergency department physicians' decisions on HIV post-exposure prophylaxis with national guidelines: results from a retrospective cohort study.

BACKGROUND: Post-exposure prophylaxis (PEP) is an effective tool to prevent infection with HIV. Patients seeking PEP after potential HIV exposure usually present to the emergency department (ED). Our study sought to determine the concordance of ED physicians' decisions on HIV-PEP with national guidelines (primary objective) and to assess the clinical relevance of drug-drug interactions (DDIs) between the HIV-PEP regimen and patients' concomitant medication (secondary objective). METHODS: We conducted a retrospective cohort study at the ED of Hannover Medical School, Germany. Between 1 January 2018 and 31 December 2019, 113 of 11 246 screened patients presented to the ED after potential HIV exposure and were enrolled in the study. RESULTS: The median age of the patients (82.3% male) was 30 y (IQR 25-35.5), 85.8% of potential HIV exposures were characterised as sexual and 85.0% presented within 72 h. ED physicians' decisions on HIV-PEP were concordant with national guidelines in 93.8%. No clinically relevant DDIs were detected. CONCLUSIONS: ED physicians' decisions on HIV-PEP were highly concordant with national guidelines. Approximately 1% of patient presentations to the ED were related to HIV exposure; therefore, training ED physicians on HIV transmission risk assessment and indications/contraindications for HIV-PEP is paramount.

Clinical-pharmacological drug information center of Hannover Medical School: experiences and analysis from a tertiary care university hospital.

Drug information centers (DICs) are institutions dedicated to provide objective, independent, and up-to-date information on drugs and their rational use. To overcome the lack of recent DIC reports from central Europe, we analyzed all queries (n = 594) submitted to the DIC run by the Institute for Clinical Pharmacology of Hannover Medical School between October 2018 and April 2022. Approximately one in three queries (31.1%; 185/594) was submitted by internists. 82.8% (492/594) of the queries were patient-specific, while the remaining 17.2% (102/594) were general queries. Adverse drug reactions (ADRs), indications/contraindications, and pharmacodynamic interactions (PDIs) represented the three most frequently addressed query categories, being involved in 44.8% (266/594), 43.3% (257/594), and 34.3% (204/594) of all queries, respectively (assignment of more than one category per query was possible). As compared to general queries, patient-specific queries were statistically significantly more often related to ADRs, PDIs, and pharmacokinetic interactions (PKIs) (ADRs: 35.3% vs. 46.7%, P = 0.034; PDIs: 14.7% vs. 38.4%, P < 0.001; PKIs: 20.6% vs. 31.5%, P = 0.028). To demonstrate the complexity of queries submitted to the clinical-pharmacological DIC, we present and comment on an illustrative selection of queries.

Predictors of response to intra-arterial vasodilatory therapy of non-occlusive mesenteric ischemia in patients with severe shock: results from a prospective observational study.

BACKGROUND: Non-occlusive mesenteric ischemia (NOMI) is a life-threatening condition occurring in patients with shock and is characterized by vasoconstriction of the mesenteric arteries leading to intestinal ischemia and multi-organ failure. Although minimal invasive local intra-arterial infusion of vasodilators into the mesenteric circulation has been suggested as a therapeutic option in NOMI, current knowledge is based on retrospective case series and it remains unclear which patients might benefit. Here, we prospectively analyzed predictors of response to intra-arterial therapy in patients with NOMI. METHODS: This is a prospective single-center observational study to analyze improvement of ischemia (indicated by reduction of blood lactate > 2 mmol/l from baseline after 24 h, primary endpoint) and 28-day mortality (key secondary endpoint) in patients with NOMI undergoing intra-arterial vasodilatory therapy. Predictors of response to therapy concerning primary and key secondary endpoint were identified using a) clinical parameters as well as b) data from 2D-perfusion angiography and c) experimental biomarkers of intestinal injury. RESULTS: A total of 42 patients were included into this study. At inclusion patients had severe shock, indicated by high doses of norepinephrine (NE) (median (interquartile range (IQR)) 0.37 (0.21-0.60) µg/kg/min), elevated lactate concentrations (9.2 (5.2-13) mmol/l) and multi-organ failure. Patients showed a continuous reduction of lactate following intra-arterial prostaglandin infusion (baseline: (9.2 (5.2-13) mmol/l vs. 24 h: 4.4 (2.5-9.1) mmol/l, p < 0.001) with 22 patients (52.4%) reaching a lactate reduction > 2 mmol/l at 24 h following intervention. Initial higher lactate concentrations and lower NE doses at baseline were independent predictors of an improvement of ischemia. 28-day mortality was 59% in patients with a reduction of lactate > 2 mmol/l 24 h after inclusion, while it was 85% in all other patients (hazard ratio 0.409; 95% CI, 0.14-0.631, p = 0.005). CONCLUSIONS: A reduction of lactate concentrations was observed following implementation of intra-arterial therapy, and lactate reduction was associated with better survival. Our findings concerning outcome predictors in NOMI patients undergoing intra-arterial prostaglandin therapy might help designing a randomized controlled trial to further investigate this therapeutic approach. Trial registration Retrospectively registered on January 22, 2020, at clinicaltrials.gov (REPERFUSE, NCT04235634), https://clinicaltrials.gov/ct2/show/NCT04235634?cond=NOMI&draw=2&rank=1 .

Targeting the "sweet spot" in septic shock - A perspective on the endothelial glycocalyx regulating proteins Heparanase-1 and -2.

Sepsis is a life-threatening syndrome caused by a pathological host response to an infection that eventually, if uncontrolled, leads to septic shock and ultimately, death. In sepsis, a massive aggregation of pathogen-associated molecular patterns (PAMPs) and damage-associated molecular patterns (DAMPs) cause a cytokine storm. The endothelial glycocalyx (eGC) is a gel like layer on the luminal side of the endothelium that consists of proteoglycans, glycosaminoglycans (GAG) and plasma proteins. It is synthesized by endothelial cells and plays an active role in the regulation of inflammation, permeability, and coagulation. In sepsis, early and profound injury of the eGC is observed and circulating eGC components correlate directly with clinical severity and outcome. The activity of the heparan sulfate (HS) specific glucuronidase Heparanase-1 (Hpa-1) is elevated in sepsis, resulting in shedding of heparan sulfate (HS), a main GAG of the eGC. HS induces endothelial barrier breakdown and accelerates systemic inflammation. Lipopolysaccharide (LPS), a PAMP mainly found on the surface of gram-negative bacteria, activates TLR-4, which results in cytokine production and further activation of Hpa-1. Hpa-1 shed HS fragments act as DAMPs themselves, leading to a vicious cycle of inflammation and end-organ dysfunction such as septic cardiomyopathy and encephalopathy. Recently, Hpa-1's natural antagonist, Heparanase-2 (Hpa-2) has been identified. It has no intrinsic enzymatic activity but instead acts by reducing inflammation. Hpa-2 levels are reduced in septic mice and patients, leading to an acquired imbalance of Hpa-1 and Hpa-2 paving the road towards a therapeutic intervention. Recently, the synthetic antimicrobial peptide 19-2.5 was described as a promising therapy protecting the eGC by inhibition of Hpa-1 activity and HS shed fragments in animal studies. However, a recombinant Hpa-2 therapy does not exist to the present time. Therapeutic plasma exchange (TPE), a modality already tested in clinical practice, effectively removes injurious mediators, e.g., Hpa-1, while replacing depleted protective molecules, e.g., Hpa-2. In critically ill patients with septic shock, TPE restores the physiological Hpa-1/Hpa-2 ratio and attenuates eGC breakdown. TPE results in a significant improvement in hemodynamic instability including reduced vasopressor requirement. Although promising, further studies are needed to determine the therapeutic impact of TPE in septic shock.

Effects of therapeutic plasma exchange on the endothelial glycocalyx in septic shock.

BACKGROUND: Disruption of the endothelial glycocalyx (eGC) is observed in septic patients and its injury is associated with multiple-organ failure and inferior outcomes. Besides this biomarker function, increased blood concentrations of shedded eGC constituents might play a mechanistic role in septic organ failure. We hypothesized that therapeutic plasma exchange (TPE) using fresh frozen plasma might influence eGC-related pathology by removing injurious mediators of eGC breakdown while at the time replacing eGC protective factors. METHODS: We enrolled 20 norepinephrine-dependent (NE > 0.4 µg/kg/min) patients with early septic shock (onset < 12 h). Sublingual assessment of the eGC via sublingual sidestream darkfield (SDF) imaging was performed. Plasma eGC degradation products, such as heparan sulfate (HS) and the eGC-regulating enzymes, heparanase (Hpa)-1 and Hpa-2, were obtained before and after TPE. A 3D microfluidic flow assay was performed to examine the effect of TPE on eGC ex vivo. Results were compared to healthy controls. RESULTS: SDF demonstrated a decrease in eGC thickness in septic patients compared to healthy individuals (p = 0.001). Circulating HS levels were increased more than sixfold compared to controls and decreased significantly following TPE [controls: 16.9 (8-18.6) vs. septic patients before TPE: 105.8 (30.8-143.4) µg/ml, p < 0.001; vs. after TPE: 70.7 (36.9-109.5) µg/ml, p < 0.001]. The Hpa-2 /Hpa-1 ratio was reduced in septic patients before TPE but normalized after TPE [controls: 13.6 (6.2-21.2) vs. septic patients at inclusion: 2.9 (2.1-5.7), p = 0.001; vs. septic patients after TPE: 13.2 (11.2-31.8), p < 0.001]. Ex vivo stimulation of endothelial cells with serum from a septic patient induced eGC damage that could be attenuated with serum from the same patient following TPE. CONCLUSIONS: Septic shock results in profound degradation of the eGC and an acquired deficiency of the protective regulator Hpa-2. TPE removed potentially injurious eGC degradation products and partially attenuated Hpa-2 deficiency. Trial registration clinicaltrials.gov NCT04231994, retrospectively registered 18 January 2020.

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.

Modulation of the Permeability-Inducing Factor Angiopoietin-2 Through Bifonazole in Systemic Inflammation.

BACKGROUND: Vascular barrier breakdown in sepsis represents a key component of the maladaptive host response to infection and the release of endothelial Angiopoietin-2 (Angpt-2) is a mechanistic driver of endothelial hyperpermeability. Angpt-2 is associated with morbidity and mortality but a targeted therapeutic approach is not available. We screened for U.S. Food and Drug Administration (FDA) approved drugs that might have off-target effects decreasing Angpt-2 and therefore, ameliorating capillary leakage. METHODS: Endothelial cells were isolated from human umbilical veins (HUVECs) and used for in vitro studies at baseline and after stimulation (FDA-library screening, RT-PCR, ELISA, immunocytochemistry, MTT assay). On the functional level, we assessed real-time transendothelial electrical resistance (TER) using an electric cell-substrate impedance sensing device. RESULTS: We found that the anti-fungal Bifonazole (BIFO) reduces spontaneous Angpt-2 release in a time- and dose-dependent manner after 8, 12, and 24 h (24 h: veh: 15.6 ±â€Š0.7 vs. BIFO: 8.6 ±â€Š0.8 ng/mL, P < 0.0001). Furthermore, we observed a reduction in its intra-cellular content by 33% (P < 0.001). Stimulation with tumor necrosis factor α induced a strong release of Angpt-2 that could analogously be blocked by additional treatment with BIFO (veh: 1.58 ±â€Š0.2 vs. BIFO: 1.02 ±â€Š0.1, P < 0.0001). Quantification of endothelial permeability by TER revealed that BIFO was sufficient to reduce Thrombin-induced barrier breakdown (veh: 0.82 ±â€Š0.1 vs. BIFO: 1.01 ±â€Š0.02, P < 0.05). CONCLUSION: The antifungal BIFO reduces both release and biosynthesis of the endothelial-destabilizing factor Angpt-2 in vitro thereby improving vascular barrier function. Additional studies are needed to further investigate the underlying mechanism and to translate these findings to in vivo models.

Role of endothelial microRNA 155 on capillary leakage in systemic inflammation.

BACKGROUND: Capillary leakage is a key contributor to the pathological host response to infections. The underlying mechanisms remain incompletely understood, and the role of microRNAs (MIR) has not been investigated in detail. We hypothesized that specific MIRs might be regulated directly in the endothelium thereby contributing to vascular leakage. METHODS: SmallRNA sequencing of endotoxemic murine pulmonary endothelial cells (ECs) was done to detect regulated vascular MIRs. In vivo models: transgenic zebrafish (flk1:mCherry/l-fabp:eGFP-DPB), knockout/wildtype mouse (B6.Cg-Mir155tm1.1Rsky/J); disease models: LPS 17.5 mg/kgBW and cecal ligation and puncture (CLP); in vitro models: stimulated human umbilical vein EC (HUVECs), transendothelial electrical resistance. RESULTS: Endothelial MIR155 was identified as a promising candidate in endotoxemic murine pulmonary ECs (25 × upregulation). Experimental overexpression in a transgenic zebrafish line and in HUVECs was sufficient to induce spontaneous vascular leakage. To the contrary, genetic MIR155 reduction protects against permeability both in vitro and in endotoxemia in vivo in MIR155 heterozygote knockout mice thereby improving survival by 40%. A tight junction protein, Claudin-1, was down-regulated both in endotoxemia and by experimental MIR155 overexpression. Translationally, MIR155 was detectable at high levels in bronchoalveolar fluid of patients with ARDS compared to healthy human subjects. CONCLUSIONS: We found that MIR155 is upregulated in the endothelium in mouse and men as part of a systemic inflammatory response and might contribute to the pathophysiology of vascular leakage in a Claudin-1-dependent manner. Future studies have to clarify whether MIR155 could be a potential therapeutic target.