Acute hypoxic respiratory failure due to Lenalidomide-induced interstitial pneumonitis in a patient with multiple myeloma.

BACKGROUND: Patients with multiple myeloma are immunosuppressed due to both the disease itself and immunosuppressive therapies. Thus, when presenting with respiratory failure and pulmonary opacities, pneumonia must be considered. However, while rare, immunomodulating medications used in the treatment of multiple myeloma can also cause potentially life-threatening respiratory failure, a distinction which has important treatment implications. CASE PRESENTATION: An 80-year-old male with recently diagnosed multiple myeloma undergoing treatment with lenalidomide and daratumumab presented with acute, rapidly progressive hypoxic respiratory failure ultimately requiring intubation and mechanical ventilatory support. Imaging revealed bilateral pulmonary opacities, however infectious workup was negative, and he was ultimately diagnosed with lenalidomide-induced interstitial pneumonitis, a rare but serious adverse effect of this medication. He was treated with drug discontinuation and methylprednisolone, and quickly recovered. CONCLUSION: Lenalidomide is an immunomodulating medication used in the treatment of multiple myeloma, and is associated with rare but serious cases of drug-induced interstitial pneumonitis. Thus, if a patient receiving lenalidomide develops shortness of breath and/or hypoxia, drug-induced pneumonitis must be on the differential. Permanent drug discontinuation with or without corticosteroids is the mainstay of treatment, and patients are often able to fully recover, underscoring the need for early recognition of this condition.

The safety of remimazolam versus propofol in gastroscopic sedation: a meta-analysis.

BACKGROUND: This meta-analysis was designed to compare the safety and efficiency of remimazolam with those of propofol in patients undergoing gastroscope sedation. METHODS: We searched PubMed, Cochrane Library, Embase, Ovid, Wanfang Database, China National Knowledge Infrastructure, SINOMED, and ClinicalTrials.gov for studies that reported on remimazolam versus propofol for gastroscope sedation from establishment to February 25, 2023. The sedative efficiency and the incidence of adverse events were assessed as outcomes. Version 2 of the Cochrane risk-of-bias assessment tool was used to assess the risk of bias. Review Manager 5.4 and STATA 17 were used to perform all statistical analyses. RESULTS: A total of 26 randomized controlled trials involving 3,641 patients were included in this meta-analysis. The results showed that remimazolam had a significantly lower incidence of respiratory depression (risk ratio [RR] = 0.40, 95% confidence interval [CI]: 0.28-0.57; p < 0.01, GRADE high), hypoxemia (RR = 0.34, 95% CI: 0.23-0.49; p < 0.01, GRADE high), bradycardia (RR = 0.34, 95% CI: 0.23-0.51; p < 0.01, GRADE high), dizziness (RR = 0.45, 95% CI: 0.31-0.65; p < 0.01, GRADE high), injection site pain (RR = 0.06, 95% CI: 0.03-0.13; p < 0.01, GRADE high), nausea or vomiting (RR = 0.79, 95% CI: 0.62-1.00; p = 0.05, GRADE moderate), and hypotension (RR = 0.36, 95% CI: 0.26-0.48; p < 0.01, GRADE low). CONCLUSIONS: Remimazolam can be used safely in gastroscopic sedation and reduces the incidence of respiratory depression, hypoxemia, bradycardia, injection site pain, and dizziness compared with propofol, and doesn't increase the incidence of nausea and vomiting.

Transmigrating neutrophils shape the mucosal microenvironment through localized oxygen depletion to influence resolution of inflammation.

Acute intestinal inflammation involves early accumulation of neutrophils (PMNs) followed by either resolution or progression to chronic inflammation. Based on recent evidence that mucosal metabolism influences disease outcomes, we hypothesized that transmigrating PMNs influence the transcriptional profile of the surrounding mucosa. Microarray studies revealed a cohort of hypoxia-responsive genes regulated by PMN-epithelial crosstalk. Transmigrating PMNs rapidly depleted microenvironmental O2 sufficiently to stabilize intestinal epithelial cell hypoxia-inducible factor (HIF). By utilizing HIF reporter mice in an acute colitis model, we investigated the relative contribution of PMNs and the respiratory burst to "inflammatory hypoxia" in vivo. CGD mice, lacking a respiratory burst, developed accentuated colitis compared to control, with exaggerated PMN infiltration and diminished inflammatory hypoxia. Finally, pharmacological HIF stabilization within the mucosa protected CGD mice from severe colitis. In conclusion, transcriptional imprinting by infiltrating neutrophils modulates the host response to inflammation, via localized O2 depletion, resulting in microenvironmental hypoxia and effective inflammatory resolution.

Peri-Intubation Hypoxia After Delayed Versus Rapid Sequence Intubation in Critically Injured Patients on Arrival to Trauma Triage: A Randomized Controlled Trial.

BACKGROUND: Critically injured patients who are agitated and delirious on arrival do not allow optimal preoxygenation in the emergency area. We investigated whether the administration of intravenous (IV) ketamine 3 minutes before administration of a muscle relaxant is associated with better oxygen saturation levels while intubating these patients. METHODS: Two hundred critically injured patients who required definitive airway management on arrival were recruited. The subjects were randomized as delayed sequence intubation (group DSI) or rapid sequence intubation (group RSI). In group DSI, patients received a dissociative dose of ketamine followed by 3 minutes of preoxygenation and paralysis using IV succinylcholine for intubation. In group RSI, a 3-minute preoxygenation was performed before induction and paralysis using the same drugs, as described conventionally. The primary outcome was incidence of peri-intubation hypoxia. Secondary outcomes were first-attempt success rate, use of adjuncts, airway injuries, and hemodynamic parameters. RESULTS: Peri-intubation hypoxia was significantly lower in group DSI (8 [8%]) compared to group RSI (35 [35%]; P = .001). First-attempt success rate was higher in group DSI (83% vs 69%; P = .02). A significant improvement in mean oxygen saturation levels from baseline values was seen in group DSI only. There was no incidence of hemodynamic instability. There was no statistically significant difference in airway-related adverse events. CONCLUSIONS: DSI appears promising in critically injured trauma patients who do not allow adequate preoxygenation due to agitation and delirium and require definitive airway on arrival.

Application of low-dose etomidate combined with oxycodone and midazolam in endoscopic injection sclerotherapy.

OBJECTIVE: To evaluate the adverse effects and particularly the anesthetic effect of low-dose etomidate combined with oxycodone and midazolam in endoscopic injection sclerotherapy. MATERIALS AND METHODS: We herein report a prospective, double-blind, randomized controlled trial. It included patients with liver cirrhosis (age, 18 - 65 years; BMI, 18 - 25 kg/m2) who were treated with endoscopic injection sclerotherapy, and the patients were randomly assigned to the propofol group or the etomidate group. The incidence of respiratory depression was the primary outcome measure. The occurrence of various adverse effects and endoscopist satisfaction score were the secondary outcome measures. RESULTS: In this study, we enrolled a total of 96 patients. The incidence of respiratory depression in the propofol group was 19%, while that in the etomidate group was only 4% (9/47 vs. 2/49; p = 0.026). Regarding the secondary outcome measures, the incidence of hypoxia in the propofol group was 15%, while that in the etomidate group was only 2% (7/47 vs. 1/49; p = 0.029). Injection-site pain occurred in 0% and 23% of the patients in the etomidate group and propofol group, respectively (p < 0.001). Endoscopist satisfaction scores were classified as "poor", "fair", "good", and "very good". The scores were 17% higher (46/49 vs. 36/47; p = 0.026) for the "very good" level and 15% lower (3/49 vs. 10/47; p = 0.038) for the "good" level in the etomidate group than in the propofol group. CONCLUSION: Low-dose etomidate combined with oxycodone and midazolam for endoscopic injection sclerotherapy could reduce the incidence of hypoxia without increasing the incidence of complications.

Association of Hypoxia-Inducible Factor Prolyl Hydroxylase Inhibitors with Cardiovascular Events and Death in Dialysis Patients: A Systematic Review and Meta-Analysis.

BACKGROUND: Anemia is a common finding among patients with advanced chronic kidney disease, especially those on dialysis. The recent introduction of hypoxia-inducible factor prolyl hydroxylase inhibitors (HIF-PHIs) has raised some concerns about the cardiovascular and thrombotic complications of this class of drugs. OBJECTIVES: This meta-analysis aimed to assess the safety of HIF-PHIs in patients with end-stage kidney disease (ESKD) versus standard therapy with erythropoiesis-stimulating agents (ESAs). METHODS: Databases were searched on April 2022. Studies that reported incidence of all-cause mortality; major cardiovascular adverse events (MACEs); myocardial infarction (MI); stroke and thrombotic events in the use of HIF-PHIs or ESA on ESKD patients in hemodialysis or peritoneal dialysis were evaluated. Data were extracted from published reports, and quality assessment was performed per Cochrane recommendations. RESULTS: 12,821 patients from ten randomized controlled trials were included in this study. Most patients (83%) were on hemodialysis. 6,461 (50.3%) were using HIF-PHIs, and 6,360 (49.6%) were in the ESA group. The pooled estimated incidence of all-cause mortality was 769 in the HIF-PHIs group (relative-risk ratios (RR): 1.04; confidence interval (CI): 0.95-1.14; p = 0.52; I2 = 0%). There was no difference in the groups regarding the outcomes of MACE in the analysis of the three studies that reported this outcome (RR: 0.95; CI: 0.87-1.04; p = 0.69; I2 = 0%). In addition, there was no statistical difference among the outcomes of MI, stroke, or thrombotic events. CONCLUSIONS: Among patients with ESKD on dialysis, the use of HIF-PHIs was non-inferior regarding the safety outcomes when compared to standard of care therapy.

Comparison of remifentanil and esketamine in combination with propofol for patient sedation during fiberoptic bronchoscopy.

BACKGROUND: Ideal sedation and analgesia strategies for fiberoptic bronchoscopy have not been found. At present, propofol based sedation strategy still has some defects, such as respiratory depression and blood pressure drop. It is difficult to meet the requirements of safety and effectiveness at the same time. The aim of this study was to compare the clinical efficacy of propofol/remifentanil with propofol/esketamine for patient sedation during fiberoptic bronchoscopy. METHOD: Patients undergoing fiberoptic bronchoscopy were randomly assigned to propofol/ remifentanil (PR group; n = 42) or propofol/esketamine (PK group; n = 42) for sedation and analgesia. The primary outcome was the rate of transient hypoxia (oxygen saturation (SpO2) < 95%). The secondary outcomes are the intraoperative hemodynamics, including the changes in blood pressure, heart rate, the incidence of adverse reactions, the total amount of propofol usage were recorded, and the satisfaction level of patients and bronchoscopists. RESULTS: After sedation, the arterial pressure and heart rate of patients in the PK group were stable without significant decrease. Decreases in diastolic blood pressure, mean arterial pressure, and heart rate were observed in patients in the PR group (P < 0.05), although it was not of clinical relevance. The dosage of propofol in the PR group was significantly higher than that in the PK group (144 ± 38 mg vs. 125 ± 35 mg, P = 0.012). Patients in the PR group showed more transient hypoxia (SpO2 < 95%) during surgery (7 vs. 0, 0% versus 16.6%, P = 0.018), more intraoperative choking (28 vs. 7, P < 0.01), postoperative vomiting (22 vs. 13, P = 0.076) and vertigo (15 vs. 13, P = 0.003). Bronchoscopists in the PK group showed more satisfaction. CONCLUSION: Compared with remifentanil, the combination of esketamine with propofol in fiberoptic bronchoscopy leaded to more stable intraoperative hemodynamics, lower dosage of propofol, lower transient hypoxia rate, fewer incidence of adverse events, and greater bronchoscopists satisfaction.

Pentoxifylline inhibits phosgene-induced lung injury via improving hypoxia.

Inhalation of high concentrations of phosgene often causes pulmonary edema, which obstructs the airway and causes tissue hypoxia. There is currently no specific antidote. This study was performed to investigate the effect behind pentoxifylline (PTX) treatment for phosgene-induced lung injury in rat models. Rats were exposed to phosgene. The protein levels of hypoxia-inducible factor-1α (HIF-1α), vascular endothelial growth factor (VEGF), and occludin proteins in lung tissue were determined. The effect of both prophylactic and therapeutic administration of PTX (50 mg/kg and 100 mg/kg) was evaluated. The lung permeability index and HIF-1α protein level increased, the arterial blood oxygenation index (PaO2/FIO2 ratio) and occludin protein level decreased significantly 6 h after phosgene exposure (P < 0.05). PTX exerted protective effects by HIF-1α-VEGF-occludin signaling pathway to some extent. Moreover, prophylactic, but not therapeutic administration of PTX (100 mg/kg), exhibited a significant protective effect. Pretreatment with PTX protected against phosgene-induced lung injury, possibly by inhibiting differential expression of HIF-1α, VEGF, and occludin.

Demand-only patient-controlled analgesia for treatment of acute vaso-occlusive pain in sickle cell disease.

BACKGROUND: Sickle cell disease (SCD) is a chronic illness that is associated with frequent admissions for vaso-occlusive episodes (VOE). Opioids are frequently utilized in pain management, but dosing is often provider dependent. Opioids cause both short-term and long-term side effects, so the minimal effective dose is desired. This study examined demand-only patient-controlled analgesia (PCA) in pediatric patients. METHODS: A new clinical practice guideline (CPG) for a single institution was implemented, which eliminated basal infusion dosing for PCAs on hospital admission. The primary aim of this retrospective study was to evaluate length of stay (LOS) before and after implementation of a CPG of demand-only PCA and, in a selected subpopulation, addition of short-term methadone. Secondary aims included opioid utilization, acute chest syndrome (ACS), and hypoxia. Inclusion criteria included SCD, ≤21 years of age, uncomplicated VOE admission, and ≥ 3 and ≤ 8 hospital admissions for SCD pain control within one calendar year. RESULTS: LOS decreased postintervention (7.2 ± 5.1 vs 4.5 ± 3.8 days, P < 0.001). Mean total opioid utilization in morphine equivalents mg/kg markedly decreased between the cohorts (13.3 ± 33.8 vs 3.6 ± 3.0, P < 0.001). ACS (21.9% vs 2.8%, P = 0.004) and hypoxia (28% vs 6.9%, P< 0.001) decreased significantly as well. CONCLUSION: Bolus PCA dosing of opioids resulted in decreased LOS and reductions in opioid utilization, hypoxia, and ACS.

Puerarin-V prevents the progression of hypoxia- and monocrotaline-induced pulmonary hypertension in rodent models.

Pulmonary hypertension (PH) is a cardiopulmonary disease characterized by a progressive increase in pulmonary vascular resistance. One of the initial pathogenic factors of PH is pulmonary arterial remodeling under various stimuli. Current marketed drugs against PH mainly relieve symptoms without significant improvement in overall prognosis. Discovering and developing new therapeutic drugs that interfere with vascular remodeling is in urgent need. Puerarin is an isoflavone compound extracted from the root of Kudzu vine, which is widely used in the treatment of cardiovascular diseases. In the present study, we evaluated the efficacy of puerarin in the treatment of experimental PH. PH was induced in rats by a single injection of MCT (50 mg/kg, sc), and in mice by exposure to hypoxia (10% O2) for 14 days. After MCT injection the rats were administered puerarin (10, 30, 100 mg · kg-1 · d-1, i.g.) for 28 days, whereas hypoxia-treated mice were pre-administered puerarin (60 mg · kg-1 · d-1, i.g.) for 7 days. We showed that puerarin administration exerted significant protective effects in both experimental PH rodent models, evidenced by significantly reduced right ventricular systolic pressure (RVSP) and lung injury, improved pulmonary artery blood flow as well as pulmonary vasodilation and contraction function, inhibited inflammatory responses in lung tissues, improved resistance to apoptosis and abnormal proliferation in lung tissues, attenuated right ventricular injury and remodeling, and maintained normal function of the right ventricle. We revealed that MCT and hypoxia treatment significantly downregulated BMPR2/Smad signaling in the lung tissues and PPARγ/PI3K/Akt signaling in the lung tissues and right ventricles, which were restored by puerarin administration. In addition, we showed that a novel crystal type V (Puer-V) exerted better therapeutic effects than the crude form of puerarin (Puer). Furthermore, Puer-V was more efficient than bosentan (a positive control drug) in alleviating the abnormal structural changes and dysfunction of lung tissues and right ventricles. In conclusion, this study provides experimental evidence for developing Puer-V as a novel therapeutic drug to treat PH.

Mucus Plugs and Emphysema in the Pathophysiology of Airflow Obstruction and Hypoxemia in Smokers.

Rationale: The relative roles of mucus plugs and emphysema in mechanisms of airflow limitation and hypoxemia in smokers with chronic obstructive pulmonary disease (COPD) are uncertain.Objectives: To relate image-based measures of mucus plugs and emphysema to measures of airflow obstruction and oxygenation in patients with COPD.Methods: We analyzed computed tomographic (CT) lung images and lung function in participants in the Subpopulations and Intermediate Outcome Measures in COPD Study. Radiologists scored mucus plugs on CT lung images, and imaging software automatically quantified emphysema percentage. Unadjusted and adjusted relationships between mucus plug score, emphysema percentage, and lung function were determined using regression.Measurements and Main Results: Among 400 smokers, 229 (57%) had mucus plugs and 207 (52%) had emphysema, and subgroups could be identified with mucus-dominant and emphysema-dominant disease. Only 33% of smokers with high mucus plug scores had mucus symptoms. Mucus plug score and emphysema percentage were independently associated with lower values for FEV1 and peripheral oxygen saturation (P < 0.001). The relationships between mucus plug score and lung function outcomes were strongest in smokers with limited emphysema (P < 0.001). Compared with smokers with low mucus plug scores, those with high scores had worse COPD Assessment Test scores (17.4 ± 7.7 vs. 14.4 ± 13.3), more frequent annual exacerbations (0.75 ± 1.1 vs. 0.43 ± 0.85), and shorter 6-minute-walk distance (329 ± 115 vs. 392 ± 117 m) (P < 0.001).Conclusions: Symptomatically silent mucus plugs are highly prevalent in smokers and independently associate with lung function outcomes. These data provide rationale for targeting patients with mucus-high/emphysema-low COPD in clinical trials of mucoactive treatments.Clinical trial registered with www.clinicaltrials.gov (NCT01969344).

Hypoxic respiratory distress potentially secondary to phosphorus trifluoride gas exposure.

We herein report a rare, probable exposure of a patient to phosphorus trifluoride gas. The objective of this case report is to highlight the potential exposure to phosphorus trifluoride gas and discuss the best management of it. A 48-year-old worker at a specialty gases laboratory was transported to the community Emergency Department (ED) in respiratory distress, presenting with peripheral cyanosis, an unobtainable oxygen saturation, chocolate-colored blood, and a Glasgow coma scale of 15. A non-rebreather was placed, poison control was contacted, and the patient was administered empiric methylene blue intravenously due to worsening cyanosis and respiratory distress. Upon arrival at the academic facility, the patient was no longer cyanotic and reported improvement of his symptoms. The patient's employer informed staff that a canister of phosphorus trifluoride gas in his workstation was found to be empty but should have been full. It was also discovered that a coworker left work early the same day with similar but milder symptoms. Hyperbaric oxygen therapy was considered; however, the patient was improving on oxygen via non-rebreather, and he had no other indications. Because the patient continued to require supplemental oxygen to maintain their oxygen saturation above 92%, he was admitted to the ICU and treated with prednisone daily for chemical pneumonitis. After 4 days, he successfully transitioned to room air without hypoxia. While exposures such as this do not occur frequently, it is important to maintain a broad differential and treatment plan as we continue to investigate the etiology and best treatment option.

Decreasing the Incidence of Hypoxia and Airway Maneuvers During GI Procedures.

Many outpatient gastrointestinal procedures are completed with propofol anesthesia. A side effect of propofol is airway obstruction and subsequent hypoxia. This study was designed to determine whether the use of a high-flow nasal cannula is associated with a decreased incidence of hypoxia or airway obstruction in patients undergoing propofol sedation in the gastrointestinal laboratory with a STOP-BANG score ≥5. High-flow nasal cannula was administered at 70 L/min on 27 patients with a STOP-BANG score ≥5 receiving monitored anesthesia care sedation for an esophagogastroduodenoscopy, endoscopic ultrasound, or colonoscopy procedure. Patients were compared to a group from a previous project without the use of high-flow nasal cannula assessing whether hypoxia, apnea, or the need for airway maneuvers occurred. The non-high-flow nasal cannula group required an airway maneuver 53.3% (n = 8) whereas the high-flow nasal cannula group required an airway maneuver 18.5% (n = 5) (p = .021). High-flow nasal cannula was associated with a reduced need for airway maneuvers in patients with a high risk of obstructive sleep apnea undergoing propofol-assisted procedures.

Left ventricular depression and pulmonary edema in rats after short-term normobaric hypoxia: effects of adrenergic blockade and reduced fluid load.

Acute normobaric hypoxia may induce pulmonary injury with edema (PE) and inflammation. Hypoxia is accompanied by sympathetic activation. As both acute hypoxia and high plasma catecholamine levels may elicit PE, we had originally expected that adrenergic blockade may attenuate the severity of hypoxic pulmonary injury. In particular, we investigated whether administration of drugs with reduced fluid load would be beneficial with respect to both cardiocirculatory and pulmonary functions in acute hypoxia. Rats were exposed to normobaric hypoxia (10% O2) over 1.5 or 6 h and received 0.9% NaCl or adrenergic blockers either as infusion (1 ml/h, increased fluid load) or injection (0.5 ml, reduced fluid load). Control animals were kept in normoxia and received infusions or injections of 0.9% NaCl. After 6 h of hypoxia, LV inotropic function was maintained with NaCl injection but decreased significantly with NaCl infusion. Adrenergic blockade induced a similar LV depression when fluid load was low, but did not further deteriorate LV depression after 6 h of infusion. Reduced fluid load also attenuated pulmonary injury after 6 h of hypoxia. This might be due to an effective fluid drainage into the pleural space. Adrenergic blockade could not prevent PE. In general, increased fluid load and impaired LV inotropic function promote the development of PE in acute hypoxia. The main physiologic conclusion from this study is that fluid reduction under hypoxic conditions has a protective effect on cardiopulmonary function. Consequently, appropriate fluid management has particular importance to subjects in hypoxic conditions.

Vandetanib-eluting radiopaque beads for chemoembolization: physicochemical evaluation and biological activity of vandetanib in hypoxia.

Vandetanib-eluting radiopaque beads (VERB) have been developed for use in transarterial chemoembolization of liver tumours, with the goal of combining embolization with local delivery of antiangiogenic therapy. The objective of this study was to investigate how embolization-induced hypoxia may affect antitumoural activity of vandetanib, an inhibitor of vascular endothelial growth factor receptor (VEGFR) and epidermal growth factor receptor (EGFR), in the context of hepatocellular carcinoma (HCC) treatment. We studied the effect of vandetanib on proliferation, cell cycle and apoptosis of HCC cells, in hypoxic conditions, as well as the direct effects of the beads on 3D HCC spheroids. Vandetanib suppressed proliferation and induced apoptosis of HCC cells in vitro and was equipotent in hypoxic and normoxic conditions. High degrees of apoptosis were observed among cell lines in which vandetanib suppressed ERK1/2 phosphorylation and upregulated the proapoptotic protein Bim, but this did not appear essential for vandetanib-induced cell death in all cell lines. Vandetanib also suppressed the hypoxia-induced secretion of VEGF from HCC cells and inhibited proliferation of endothelial cells. Incubation of tumour spheroids with VERB led to sustained growth inhibition equivalent to the effect of free drug. We conclude that vandetanib has both antiangiogenic and direct anticancer activity against HCC cells even in hypoxic conditions, warranting the further evaluation of VERB as novel anticancer agents.

Effect of Intravenous Acetaminophen on Mean Arterial Blood Pressure: A Post Hoc Analysis of the EFfect of Intravenous ACetaminophen on PosToperative HypOxemia After Abdominal SurgeRy Trial.

BACKGROUND: Acetaminophen is commonly used as part of multimodal analgesia for acute pain. The intravenous formulation offers a more predictable bioavailability compared to oral and rectal acetaminophen. There have been reports of hypotension with intravenous acetaminophen attributable to centrally mediated and vasodilatory effects. We tested the hypothesis that in adults having abdominal surgery the use of intravenous acetaminophen versus placebo for postoperative pain management is associated with a decrease in mean arterial pressure (MAP) after its administration. METHODS: This is a substudy of eFfect of intravenous ACetaminophen on posToperative hypOxemia after abdominal surgeRy (FACTOR) trial (NCT02156154). FACTOR trial randomly assigned adults undergoing abdominal surgery to either 1 g of acetaminophen or placebo every 6 hours during the first postoperative 48 hours. Continuous monitoring of blood pressure was obtained by noninvasive ViSi Mobile device (Sotera Wireless, Inc, San Diego, CA) at 15-second intervals during initial 48 hours postoperatively. We excluded patients without continuous monitoring data available. The primary outcome was the MAP difference between MAP 5 minutes before study drug administration (baseline) and MAP 30 minutes poststudy drug administration initiation. We used a linear mixed effects model to assess the treatment effect on MAP change. The secondary outcome was MAP area under baseline (AUB) during the 30 minutes after treatment. In a sensitivity analysis of change in MAP from predrug to postdrug administration, we instead used postdrug MAP as the outcome adjusting for the baseline MAP in the model. RESULTS: Among 358 patients analyzed, 182 received acetaminophen and 176 placebo. The mean (standard deviation [SD]) of average MAP change was -0.75 (5.9) mm Hg for the treatment and 0.32 (6.3) mm Hg for the placebo. Acetaminophen was found to decrease the MAP from baseline more than placebo after drug administration. The estimated difference in mean change of MAP was -1.03 (95% confidence interval [CI] -1.60 to -0.47) mm Hg; P < .001. The sensitivity analysis showed postoperative MAP in the acetaminophen group was 1.33 (95% CI, 0.76-1.90) mm Hg lower than in the placebo group (P < .001). The median of MAP AUB was 33 [Q1 = 3.3, Q3 = 109] mm Hg × minutes for the treatment and 23 [1.6, 79] mm Hg × minutes for the placebo. Acetaminophen was found to increase the AUB with an estimated median difference of 15 (95% CI, 5-25) mm Hg × minutes (P = .003). CONCLUSIONS: Intravenous acetaminophen decreases MAP after its administration. However, this decrease does not appear to be clinically meaningful. Clinicians should not refrain to use intravenous acetaminophen for acute pain management because of worries of hypotension.

Hypoxia, oxidative stress, and immune evasion: a trinity of the trichothecenes T-2 toxin and deoxynivalenol (DON).

T-2 toxin and deoxynivalenol (DON) are type A and B trichothecenes, respectively. They widely occur as pollutants in food and crops and cause a series of toxicities, including immunotoxicity, hepatotoxicity, and neurotoxicity. Oxidative stress is the primary mechanistic basis of these toxic effects. Increasing amounts of evidence have shown that mitochondria are significant targets of apoptosis caused by T-2 toxin- and DON-induced oxidative stress via regulation of Bax/B-cell lymphoma-2 and caspase-3/caspase-9 signaling. DNA methylation and autophagy are involved in oxidative stress related to apoptosis, and hypoxia and immune evasion are related to oxidative stress in this context. Hypoxia induces oxidative stress by stimulating mitochondrial reactive oxygen species production and regulates the expression of cytokines, such as interleukin-1ß and tumor necrosis factor-α. Programmed cell death-ligand 1 is upregulated by these cytokines and by hypoxia-inducible factor-1, which allows it to bind to programmed cell death-1 to enable escape of immune cell surveillance and achievement of immune evasion. This review concentrates on novel findings regarding the oxidative stress mechanisms of the trichothecenes T-2 toxin and DON. Importantly, we discuss the new evidence regarding the connection of hypoxia and immune evasion with oxidative stress in this context. Finally, the trinity of hypoxia, oxidative stress and immune evasion is highlighted. This work will be conducive to an improved understanding of the oxidative stress caused by trichothecene mycotoxins.

Vitamin B6 prevents Isocarbophos-induced posterior cerebral artery injury in offspring rats through up-regulating S1P receptor expression.

We have previously reported that the long-term exposure of Isocarbophos, a kind of organophosphorus compounds, induces vascular dementia (VD) in rats. Studies have also shown that organophosphorus compounds have adverse effects on offsprings. Vitamin B6 is a coenzyme mainly involved in the regulation of metabolism and has been demonstrated to ameliorate VD. Sphingosine-1-phosphate (S1P), a biologically active lipid, plays a vital role in the cardiovascular system. However, whether S1P is involved in the therapeutic effects of Vitamin B6 on posterior cerebral artery injury has yet to be further answered. In the present study, we aimed to explore the potential influence of Vitamin B6 on Isocarbophos-induced posterior cerebral artery injury in offspring rats and the role of the S1P receptor in this process. We found that Vitamin B6 significantly improves the vasoconstriction function of the posterior cerebral artery in rats induced by Isocarbophos by the blood gas analysis and endothelium-dependent relaxation function assay. We further demonstrated that Vitamin B6 alleviates the Isocarbophos-induced elevation of ICAM-1, VCAM-1, IL-1, and IL-6 by using the enzyme-linked immunosorbent assay kits. By performing immunofluorescence and the western blot assay, we revealed that Vitamin B6 prevents the down-regulation of S1P in posterior cerebral artery injury. It is worth noting that Fingolimod, the S1P inhibitor, significantly inhibits the Vitamin B6-induced up-regulation of S1P in posterior cerebral artery injury. Collectively, our data indicate that Vitamin B6 may be a novel drug for the treatment of posterior cerebral artery injury and that S1P may be a drug target for its treatment.

Application of α2 -adrenergic agonists combined with anesthetics and their implication in pulmonary intravascular macrophages-insulted pulmonary edema and hypoxemia in ruminants.

Alpha2 -adrenergic agonists have been implicated in the development of pulmonary edema (PE) and sustained hypoxemia that lead to life-threatening pulmonary distress in ruminants, especially with sensitive and compromised animals. Recently, there is limited understanding of exact mechanism underlying pulmonary alterations associated with α2 -adrenergic agonist administration. Ruminants have a rich population of pulmonary intravascular macrophages (PIMs) in the pulmonary circulation, which may be involved in the development of pulmonary alveolo-capillary barrier damage. Hence, the central thesis of this review is overviewing the literatures regarding the systemic use of α2 -adrenergic agonists in domestic ruminants, focusing on their pulmonary side effects, especially on the influence of PIMs on the lung. At this moment, further studies are needed to provide a clear emphasis and better understanding of the potential role of PIMs in the lung pathophysiology associated with α2 -adrenergic agonists. These preliminary studies would be potentially to develop future medications and intervention targets that may be helpful to alleviate or prevent the critical striking pulmonary effects, and thereby improving the safety of α2 -agonist application in ruminants.

Preclinical Investigation of Trifluoperazine as a Novel Therapeutic Agent for the Treatment of Pulmonary Arterial Hypertension.

Trifluoperazine (TFP), an antipsychotic drug approved by the Food and Drug Administration, has been show to exhibit anti-cancer effects. Pulmonary arterial hypertension (PAH) is a devastating disease characterized by a progressive obliteration of small pulmonary arteries (PAs) due to exaggerated proliferation and resistance to apoptosis of PA smooth muscle cells (PASMCs). However, the therapeutic potential of TFP for correcting the cancer-like phenotype of PAH-PASMCs and improving PAH in animal models remains unknown. PASMCs isolated from PAH patients were exposed to different concentrations of TFP before assessments of cell proliferation and apoptosis. The in vivo therapeutic potential of TFP was tested in two preclinical models with established PAH, namely the monocrotaline and sugen/hypoxia-induced rat models. Assessments of hemodynamics by right heart catheterization and histopathology were conducted. TFP showed strong anti-survival and anti-proliferative effects on cultured PAH-PASMCs. Exposure to TFP was associated with downregulation of AKT activity and nuclear translocation of forkhead box protein O3 (FOXO3). In both preclinical models, TFP significantly lowered the right ventricular systolic pressure and total pulmonary resistance and improved cardiac function. Consistently, TFP reduced the medial wall thickness of distal PAs. Overall, our data indicate that TFP could have beneficial effects in PAH and support the view that seeking new uses for old drugs may represent a fruitful approach.