Blockade Group Research Articles

PSUN11 Outcomes of Nonselective or Selective Alpha-Adrenergic Antagonist for Preoperative Management of Intra-adrenal Pheochromocytoma

Abstract Background Pheochromocytoma is a rare neoplasm of the adrenal medulla that leads to catecholamine excess. Adrenalectomy is the standard management for operative candidates. Preoperative alpha-adrenergic antagonism has been traditionally performed with the non-selective irreversible agent phenoxybenzamine. Recently, use of this agent has been limited due to availability and cost. We sought to determine whether type of preoperative antihypertensive management with nonselective alpha-adrenergic antagonist or selective alpha-1 antagonist was associated with differences in patient outcomes for those undergoing adrenalectomy. Methods We performed a retrospective review of adult patients at a single institution undergoing index adrenalectomy for initial diagnosis of intra-adrenal pheochromocytoma from 2012 through 2021. Exclusion criteria were prior adrenalectomy and extra-adrenal pheochromocytoma or paraganglioma. Clinical and demographic factors were assessed. Our primary outcome was intraoperative hemodynamic stability, secondary outcomes were postoperative hemodynamic instability, and surgical complications. Data were analyzed using Chi-squared, Fisher's exact and Mann Whitney U tests. Results During the study period, 38 patients underwent index adrenalectomy for initial diagnosis of intra-adrenal pheochromocytoma. Patient age was a mean of 57.8 years (SD 13.6) with 14 male (37%) and 34 (90%) white. On preoperative cross-sectional imaging, the mean tumor size was 3.9cm (IQR 2.5–5.2) with 15 (40%) left sided, 21 (58%) right sided and 1 (3%) bilateral with 32 (87%) undergoing minimally invasive laparoscopic or robotic assisted adrenalectomy. The mean pre-contrast density on computed tomography imaging was 35.4 Hounsfield units (SD 15). Preoperative plasma metanephrines were mean 0.65 (SD 6.7), plasma normetanephrines 11.1 (SD 14.3). For preoperative pharmacologic therapy, 16 (42%) were on phenoxybenzamine, 21 (55%) selective alpha-1 antagonist, and 1 (3%) patient on both who was excluded from comparative analysis. Nine patients overall (24%) had preoperative hypertensive crisis with no difference between the groups. There was no difference between the groups for intraoperative hemodynamic instability with 6 (38%) in the phenoxybenzamine group and 10 (48%) in the selective alpha blockade group (p = 0.74) or postoperative hemodynamic instability with 5 (31%) compared with 9 (45%) respectively (p = 0.50). Groups were also similar with regard to age, sex, body mass index, comorbidities, preoperative catecholamine levels, American Society of Anesthesiologists Physical Status classification, minimally invasive or open surgery, tumor size, estimated surgical blood loss, and postoperative complications. Follow up duration was longer for the phenoxybenzamine group at 55 months (SD 35) compared with 21 months (SD 25) for the selective alpha blockade group (p = 0.003). Conclusions Use of preoperative alpha adrenergic antagonism selective alpha-1 antagonists showed similar outcomes intraoperative and postoperatively compared with irreversible nonselective alpha-adrenergic antagonists in this cohort. Use of selective alpha-1 antagonists should be considered when nonselective agents are not accessible. Presentation: Sunday, June 12, 2022 12:30 p.m. - 2:30 p.m.

Ultrasound-guided paravertebral blockade reduced perioperative opioids requirement in pancreatic resection: A randomized controlled trial

BackgroundPerioperative opioid use for pain control has been found to be associated with side effects and adverse prognosis. In this study, we hypothesized that paravertebral block could reduce the consumption of opioids during pancreatic resection surgery.MethodsWe conducted a prospective, randomized trial. Patients with resectable pancreatic cancer were randomly assigned to one of the two groups: those who received bilateral paravertebral block combined with general anesthesia [bilateral paravertebral blockade (PTB) group] or those who received only general anesthesia (Control group). The primary endpoint was the perioperative consumption of opioids (sufentanil and remifentanil). The main secondary endpoints were pain scores, complications, and serum cytokine levels.ResultsA total of 153 patients were enrolled in the study and 119 cases were analyzed. Compared to the control group, patients in PTB patients had significantly lower perioperative (30.81 vs. 56.17 µg), and intraoperative (9.58 vs. 33.67 µg) doses of sufentanil (both p < 0.001). Numerical rating scale scores of pain were comparable between the two groups. No statistical differences in complications were detected.ConclusionBilateral paravertebral block combined with general anesthesia reduced the perioperative consumption of opioids by 45%.Registration numberChiCTR1800020291 (available on http://www.chictr.org.cn/).

The Effect of a Combined Modified Pectoral and Stellate Ganglion Block on Stress and Inflammatory Response in Patients Undergoing Modified Radical Mastectomy.

Background and Aims Regional anaesthesia reports to attenuate stress and inflammatory responses associated with surgical resection; however, the effectiveness of combined nerve blocks is less often investigated. We evaluated whether a combination of a pectoral nerve block (PNB) and stellate ganglion block (SGB) is more effective than a PNB alone in reducing these responses in women undergoing modified radical mastectomy (MRM). Methods This is a prospective randomized controlled trial. Fifty patients with breast cancer were randomly allocated to receive an ultrasound-guided PNB (n = 25, PNB only group) or ultrasound-guided PNB combined with SGB (n = 25, combined blockade group). The primary outcome was perioperative plasma level of interleukin- (IL-) 6. Secondary outcomes included perioperative plasma levels of cortisol, glucose, IL-8, and tumour necrosis factor- (TNF-) α, pain scores, haemodynamic variables, sleep quality, and complications postsurgery. Results The combined blockade group exhibited significantly lower IL-6 and TNF-α levels 24 h postsurgery. Cortisol levels were significantly lower in the combined blockade group at the end of the surgery. Glucose levels at the time of incision were lower in the combined blockade group. Pain scores up to 12 h postsurgery were significantly lower in the combined blockade group, which also exhibited better perioperative haemodynamic stability. Patients in the combined blockade group reported better sleep quality on the night of surgery. Conclusion In patients undergoing MRM, PNB combined with SGB block effectively blunted perioperative inflammatory response than PNB alone. A combined block approach can also alleviate stress response and postoperative acute pain with stable perioperative haemodynamics and better postoperative sleep quality.

THE ROLE OF AP-1 TRANSCRIPTION FACTOR ACTIVATION IN THE CHANGES OF PRODUCTION AND UTILIZATION OF NITRIC OXIDE IN THE GASTRIC MUCOSA OF RATS UNDER CONDITIONS OF CHRONIC FLUORIDE INTOXICATION

Millions of people are affected by excessive fluoride intake. The effect of fluorides on the activation or inhibition of redox-sensitive transcription factors remains poorly understood. The aim of this research is to examine the effect of activation of the transcription factor AP-1 on changes in the activity of inducible NO synthase and constitutive isoforms of NO synthase, concentrations of peroxynitrites of alkali and alkaline earth metals, concentrations of nitrites and nitrosothiols in the gastric mucosa of rats under conditions of chronic fluoride intoxication. The study was conducted on 18 adult male Wistar rats weighing 220-260 g. Experimental animals were randomly divided into 3 groups of 6 animals each: control, chronic fluoride intoxication group and AP-1 transcription factor blockade group. Chronic fluoride intoxication was simulated by the administration of sodium fluoride at a dose of 10 mg / kg for 30 days. AP-1 blockade was performed by administering SR11302 at a rate of 15 mg / kg twice a week. In the gastric mucosa, the following was studied: the activities of constitutive and inducible isoforms of NO synthase, the concentration of nitrites, peroxynitrites and nitrosothiols. Chronic fluoride intoxication reduces the activity of constitutive NO synthases by 37.73% and increases the activity of inducible NO synthase by 1.61 times. The concentration of peroxynitrites increases by 2.68 times, nitrites – by 1.74 times, and nitrosothiols – by 1.88 times. Blockade of AP-1 reduces the activity of inducible isoform by 2.11, does not affect the activity of constitutive isoforms, and reduces the concentration of peroxynitrites by 1.98 times, nitrites – by 2.10 times, and nitrosothiols – by 2.37 times. Activation of the transcription factor AP-1 under conditions of chronic excessive fluoride intake leads to increased production of nitric oxide in the gastric mucosa of rats, enhances its oxidation to nitrites, promotes the formation of nitrosyl groups in the reaction with low molecular weight donors of thiol groups and increases the peroxidation of nitric oxide with the formation of peroxynitrite.

Does deep neuromuscular blockade provide improved outcomes in low pressure laparoscopic colorectal surgery? A single blinded randomized pilot study.

Low intra-abdominal pressure during laparoscopic colorectal surgery may improve outcomes and reduce hospital stay, in addition to Enhanced Recovery After Surgery (ERAS) protocols. There is concern that low pressure reduces laparoscopic vision and may increase surgical complications. Deep neuromuscular blockade may abrogate any reduction in vision of low-pressure pneumoperitoneum. However, antagonism of deep neuromuscular blockade at completion of surgery necessitates the use of sugammadex, which is prohibitively expensive, if there are no surgical benefits and warrants further study. A single institution, single blinded randomized controlled pilot study was performed comparing deep to moderate neuromuscular blockade in major laparoscopic colorectal surgery. Thirty-eight patients were randomized to deep or moderate neuromuscular blockade. There were no statistically significant differences between groups, when comparing key patient demographics, or surgeon satisfaction with view, which required increased pressure or further relaxation demands. The deep blockade group had increased QoR15 scores and a decrease in pain, C-Reactive Protein (CRP) measurements and operating times, although were non-significant. The moderate group had slightly higher incidents of Medical Emergency Team (MET) calls and more severe complications, although were non-significant. Low intra-abdominal pressure in laparoscopic colorectal surgery is feasible and allows adequate surgical visualization, regardless of the degree of neuromuscular blockade. Potential benefits of deep neuromuscular blockade may include improved pain and quality of recovery and a possible reduction of complications; however a larger cohort is required to confirm this. Future ERAS protocols may consider deep neuromuscular blockade with low intra-abdominal pressure to further benefit patients.

Comparing the Effectiveness of Bupivacaine Administration through Chest Tube and Intercostal Blockage in Patients with Rib Fractures.

There are several methods to control pain, especially in traumatic patients with rib fractures. Intrapleural analgesia (IPA) and intercostal block methods are recommended in patients with rib fractures to control pain. Here, we aimed to evaluate and compare the effects of IPA and intercostal block on patients' clinical conditions. This is a randomized clinical trial that was performed in 2020-2021 on thirty traumatic patients with rib fractures. We collected the results of arterial blood gas in all patients before interventions including HCO3, pH, pO2, and pCO2 and also evaluated pain of patients. The first group underwent intercostal blockade with standard method with bupivacaine, and for the second group of patients, a chest tube was implanted. Patients were monitored for up to 12 h for pain intensity and need for analgesics. The mean levels of HCO3 decreased in both groups after the interventions, and this decrease was more significant in patients in the intercostal blockade group (P < 0.05). The mean levels of pO2 increased in both groups after interventions, especially in patients in the intercostal blockade group (P < 0.05). The mean pCO2 levels also decreased in both groups (P < 0.05). The mean pain intensity in both groups decreased significantly after the intervention (P < 0.05) and also the mean pain intensity in the intercostal blocking group decreased significantly more than the group treated with chest tube (P < 0.05). Intercostal blockade through bupivacaine is more effective than chest tube administration of bupivacaine in patients with rib fractures.

Addition of immunotherapy to chemotherapy for metastatic triple-negative breast cancer: A systematic review and meta-analysis of randomized clinical trials.

One of the front treatment regimens used for metastatic triple-negative breast cancer (mTNBC) is treatment with programmed death-1 (PD-1) or programmed death ligand-1 (PD-L1) blockade combine with chemotherapy. However, the results of such studies have been controversial. A systematic searched of PubMed, Embase, Cochrane Library, and the proceedings of the last 5 years of several meetings until February 18, 2021. The primary endpoint was the progression-free survival (PFS) of PD-L1-positive patients treated with PD1/PD-L1 blockade plus chemotherapy compare with chemotherapy. Overall, 4 studies that included a total of 3007 mTNBC patients were analyzed in this meta-analysis. PFS was significantly improved in the PD1/PD-L1 blockade plus chemotherapy group compared with the chemotherapy group in PD-L1-positive mTNBC patients (hazard ratios, (HR), 0.69; 95% CI, 0.59-0.80; P < .001), also in intention-to-treat (ITT) population (HR, 0.82; 95% CI, 0.74-0.90; P < .001). However, no significant benefit in overall survival (OS) was observed regardless of PD-L1 status or ITT population. The immunotherapy plus chemotherapy has higher adverse events (AEs) compared with chemotherapy (all AEs, Odds ratios (ORs), 2.33; 95% CI, 1.50-3.62; P < .001; grade 3-5 AEs, OR, 1.27; 95% CI, 1.04-1.55; P = .019). This meta-analysis showed that the addition of PD1/PD-L1 blockade to chemotherapy improved PFS in PD-L1 positive mTNBC patients, also in the ITT population. However, no significant benefit in OS was observed in patients of PD-L1 positive or in the ITT population after adding PD1/PD-L1 blockade. We found a higher rate of AEs with the addition of PD1/PD-L1 blockers to chemotherapy.

ROLE OF ΚB AND AP-1 TRANSCRIPTION FACTORS IN CHANGES IN NITRIC OXIDE PRODUCTION AND UTILIZATION IN THE HEART OF RATS UNDER CHRONIC FLUORIDE INTOXICATION

Fluorides, being hazardous contaminants of soil and drinking water, can get in excessive amounts into human and animal bodies. This is especially true for regions where the fluoride content in soils is very high, for example, Poltava, Dnipropetrovsk, and Kirovohrad regions in Ukraine. Excessive fluoride intake can change the rate of nitric oxide production. The impact of fluorides on changes in nitric oxide production and metabolism in the heart and the role of redox-sensitive transcription factors in these changes are poorly understood. The aim of this study was to determine the effect of activation of κB transcription factors and activator protein 1 on the activity of inducible NO-synthase, constitutive isoforms of NO-synthase, nitrite and nitrate reductase, arginase, concentration of nitrites, peroxynitrite and nitrosothiols in the heart of rats during chronic fluoride intoxication. Materials and methods. The study was performed on 24 adult male Wistar rats weighing 220-260 grams. Animals were randomly divided into 4 groups of 6 animals in each (control, chronic fluoride intoxication group, κB blockade group and activator protein 1 blockade group). The experiment lasted 30 days. We determined the activity of inducible NO-synthase, constitutive isoforms of NO-synthase, the concentration of peroxynitrite alkali and alkaline earth metals, the concentration of nitrites and nitrosothiols, the activity of nitrite reductase, nitrate reductase and arginase. Results. Chronic fluoride intoxication increases the activity of inducible NO-synthase by 1.74 times, does not affect the activity of constitutive isoforms and reduces the activity of arginase by 35.68% compared with the control group of animals. The concentration of nitrites in the heart of rats increases 1.73 times, peroxynitrite 1.43 times, and the concentration of nitrosothiols doubled. The use of κB transcription factor blockers and activator protein 1 reduces nitric oxide production from NO synthases and reduces the concentrations of all nitric oxide metabolites in the heart of rats under conditions of chronic fluoride intoxication. Conclusions. Activation of κB transcription factors and activator protein 1 during chronic excessive intake of fluoride leads to hyperproduction of nitric oxide in the heart of rats due to increased activity of inducible NO-synthase and nitrite reductases. Excess production of nitric oxide under chronic fluoride intoxication leads to the accumulation of nitrites, peroxynitrite and nitrosothiols in the heart of rats.

Effect of anti-interleukin drugs in patients with COVID-19 and signs of cytokine release syndrome (COV-AID): a factorial, randomised, controlled trial

BackgroundInfections with SARS-CoV-2 continue to cause significant morbidity and mortality. Interleukin (IL)-1 and IL-6 blockade have been proposed as therapeutic strategies in COVID-19, but study outcomes have been conflicting. We sought to study whether blockade of the IL-6 or IL-1 pathway shortened the time to clinical improvement in patients with COVID-19, hypoxic respiratory failure, and signs of systemic cytokine release syndrome.MethodsWe did a prospective, multicentre, open-label, randomised, controlled trial, in hospitalised patients with COVID-19, hypoxia, and signs of a cytokine release syndrome across 16 hospitals in Belgium. Eligible patients had a proven diagnosis of COVID-19 with symptoms between 6 and 16 days, a ratio of the partial pressure of oxygen to the fraction of inspired oxygen (PaO2:FiO2) of less than 350 mm Hg on room air or less than 280 mm Hg on supplemental oxygen, and signs of a cytokine release syndrome in their serum (either a single ferritin measurement of more than 2000 μg/L and immediately requiring high flow oxygen or mechanical ventilation, or a ferritin concentration of more than 1000 μg/L, which had been increasing over the previous 24 h, or lymphopenia below 800/mL with two of the following criteria: an increasing ferritin concentration of more than 700 μg/L, an increasing lactate dehydrogenase concentration of more than 300 international units per L, an increasing C-reactive protein concentration of more than 70 mg/L, or an increasing D-dimers concentration of more than 1000 ng/mL). The COV-AID trial has a 2 × 2 factorial design to evaluate IL-1 blockade versus no IL-1 blockade and IL-6 blockade versus no IL-6 blockade. Patients were randomly assigned by means of permuted block randomisation with varying block size and stratification by centre. In a first randomisation, patients were assigned to receive subcutaneous anakinra once daily (100 mg) for 28 days or until discharge, or to receive no IL-1 blockade (1:2). In a second randomisation step, patients were allocated to receive a single dose of siltuximab (11 mg/kg) intravenously, or a single dose of tocilizumab (8 mg/kg) intravenously, or to receive no IL-6 blockade (1:1:1). The primary outcome was the time to clinical improvement, defined as time from randomisation to an increase of at least two points on a 6-category ordinal scale or to discharge from hospital alive. The primary and supportive efficacy endpoints were assessed in the intention-to-treat population. Safety was assessed in the safety population. This study is registered online with ClinicalTrials.gov (NCT04330638) and EudraCT (2020-001500-41) and is complete.FindingsBetween April 4, and Dec 6, 2020, 342 patients were randomly assigned to IL-1 blockade (n=112) or no IL-1 blockade (n=230) and simultaneously randomly assigned to IL-6 blockade (n=227; 114 for tocilizumab and 113 for siltuximab) or no IL-6 blockade (n=115). Most patients were male (265 [77%] of 342), median age was 65 years (IQR 54–73), and median Systematic Organ Failure Assessment (SOFA) score at randomisation was 3 (2–4). All 342 patients were included in the primary intention-to-treat analysis. The estimated median time to clinical improvement was 12 days (95% CI 10–16) in the IL-1 blockade group versus 12 days (10–15) in the no IL-1 blockade group (hazard ratio [HR] 0·94 [95% CI 0·73–1·21]). For the IL-6 blockade group, the estimated median time to clinical improvement was 11 days (95% CI 10–16) versus 12 days (11–16) in the no IL-6 blockade group (HR 1·00 [0·78–1·29]). 55 patients died during the study, but no evidence for differences in mortality between treatment groups was found. The incidence of serious adverse events and serious infections was similar across study groups.InterpretationDrugs targeting IL-1 or IL-6 did not shorten the time to clinical improvement in this sample of patients with COVID-19, hypoxic respiratory failure, low SOFA score, and low baseline mortality risk.FundingBelgian Health Care Knowledge Center and VIB Grand Challenges program.

Autoimmunity against Cardiac Self-Antigen Drives Immune Checkpoint Inhibitor-Associated Myocarditis Development

Abstract Immune checkpoint inhibitor (ICI) blocking PD-1 has been approved by the Food and Drug Administration for treatment of several types of cancers. However, fulminant myocarditis has occurred in the ICI-treated cancer patients, with low incidence but with 50 percent mortality. In this study, we investigated if PD-1 blockade can induce myocarditis in the mouse mimicking ICI-associated myocarditis in the human. We found that anti-PD-1 mAb treatment caused myocarditis development in A/J mice exhibiting enlarged heart and increased cardiac infiltration. In the cardiac infiltration, CD8+ T cells, CD4+ T cells, monocytes and macrophages were increased in the PD-1 blockade group compared to isotype control. Cardiac damage was confirmed by elevated serum level of cardiac troponin I and anti-myosin IgG. In addition, PD-1 blockade caused arrhythmia, right bundle branch block, while controls showed a normal ECG trace. The A/J mice with PD-1 blockade also developed systemic autoimmune responses such as colitis, sialadenitis, pneumonitis and myositis like immune-related adverse events in the human, supporting the immunotoxicity of PD-1 blockade. Next, using myosin-MHC tetramer staining, we found the increase of autoreactive T cells specific for cardiac myosin in the mouse heart with ICI-associated myocarditis compared to control. In the naïve heart, we were able to detect myosin-specific T cells, which number was very few but expressed a high level of PD-1. Collectively, we have developed the mouse model for human ICI-associated myocarditis and showed that the pathogenesis of this disease is an autoimmune reaction against heart-specific antigens.

EFFECT OF SEQUENTIAL NEPHRON BLOCKING IN COMPARISON WITH THE DOUBLE BLOCKADE OF THE RENIN- ANGIOTENSIN SYSTEM + BISOPROLOL ON CENTRAL SYSTOLIC BLOOD PRESSURE AND ARTERIAL STIFFNESS

Objective: The different classes of drugs routinely used in anti-hypertensive therapy promote different effects on markers of arterial stiffness and, consequently, on the central blood pressure. Arterial stiffness is the main determinant for the increase of the central blood pressure and considered an important predictor for myocardial infarction, stroke and congestive heart failure. Objective: The objective of this study was to compare the effect on the systolic central blood pressure and arterial stiffness in resistant hypertensive patients submitted to sequential nephron blockade (SNB) against double blockade of the renin-angiotensin-aldosterone system (DBRAS) plus Bisoprolol. Design and method: Fifty-five resistant hypertensive patients were recruited in the Hypertension Outpatient Clinic of FAMERP, twenty-nine in the SNB group (18F/11 M) and twenty-six in the DBRAS group (22F/4 M). Central systolic blood pressure (cSBP), incrementing index (AI) and AI75 were measured with Omron HEM9000-A. (Japan). Results: The main result showed significant reduction of the central systolic blood pressure in patients submitted to sequential blockade nephron treatment when compared with the double blockade of the renin-angiotensin system plus Bisoprolol group (128.8 ± 22.1 vs. 117.4 ± 17.9 mmHg - P = 0.03). Figure 1 Conclusions: The sequential nephron blockade group, when compared with the double blockade of the renin-angiotensin-aldosterone system plus Bisoprolol, promotes significant higher reduction of the central systolic blood pressure in resistant hypertensive patients.

Renin-Angiotensin-Aldosterone System Blockers Prior to Hospitalization and Their Association With Clinical Outcomes in Coronavirus Disease 2019 (COVID-19).

Objective: To determine the effect of angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs) use prior to hospitalization on clinical outcomes in coronavirus disease 2019 (COVID-19) patients.Design: An observational retrospective cohort study from 178 hospitals from a large health system across the United States. Patient population: Hospitalized patients (n=2726) with confirmed COVID-19 between January 1, 2020, and April 1, 2020.Main outcome(s) and measure(s): Outcomes during hospitalization, including disease severity by level of care, intensive care unit (ICU) admission, mechanical ventilator (MV) use, hospital length of stay, and in-hospital death. Patient demographics and comorbidities were also recorded.Results: A total of 2,726 patients were included in the analysis. Three hundred ninety-eight (14.6%) patients were taking an ACEI, while 352 (12.9%) patients were taking an ARB prior to hospitalization. After adjusting for comorbidities, age, renal function, and severity of illness based on level of care, ACEI prior to admission was independently associated with decreased need for MV (odds ratio [OR] 0.56, p value 0.003) and mortality (OR 0.45, p value <0.001). Similarly, patients who took ARBs were less likely to require MV when compared to the non-renin-angiotensin-aldosterone system blockade (RAASb) group (7.4% vs 12.2%, p value 0.009, respectively). ARB prior to admission was also independently associated with decreased need for MV (OR 0.46, p value 0.001) and mortality (OR 0.66, p value 0.017) compared to the non-RAASb group.Conclusion: Taking ACEIs and ARBs prior to admission for COVID-19 was independently associated with decreased need for mechanical ventilation and in-hospital mortality.

Neuromuscular blockade management and postoperative outcomes in enhanced recovery colorectal surgery: secondary analysis of POWER trial.

We evaluated the impact of neuromuscular blockade (NMB) management, monitoring and reversal on postoperative outcomes in colorectal surgical patients included in an enhanced recovery program. We performed a predefined analysis in 2084 patients undergoing elective colorectal surgery who participated in POWER study. We analyzed them for complications, length of hospital stay and mortality. Two groups were defined: 1) monitoring + reversal of the neuromuscular blockade (M+R) group: all patients receiving neuromuscular blockade monitoring plus reversal of it with any drug (neostigmine or sugammadex) were included; and 2) no monitoring nor reversal (noM+noR) group. In this group all the patients who did not receive monitoring and reversal of the neuromuscular blockade were allocated. Multivariate analysis found no statistically significant differences in moderate-severe complications (174 [25.7%] vs. 124 [27.1%]; P=0.607), length of hospital stay (10.8±11.1 vs. 11.0 ±12.6 days; P=0.683) and mortality (6 [0.9%] vs. 5 [1.1%]; P=0.840) between the group receiving optimal neuromuscular management (M+R) and the one did not receive it (noM+noR). Univariate analysis showed patients reversed with neostigmine died more than those reversed with sugammadex (3 [2.7%] vs. 3 [0.5%]; P=0.048). Our data suggest optimal neuromuscular blockade management in colorectal surgery is not associated with less moderate-severe complications, length of hospital stay or death during postoperative period in an enhanced recovery program. Neostigmine reversal seems to be linked to higher rate of mortality than sugammadex.

Comparison of Abiraterone Acetate Plus Prednisolone and Combined Androgen Blockade in High-risk Metastatic Hormone-Sensitive Prostate Cancer

Abiraterone acetate plus prednisone/prednisolone (AAP) and androgen deprivation therapy (ADT) was approved for the treatment of high-risk metastatic hormone-sensitive prostate cancer (mHSPC) in Japan in 2018. We investigated 22 patients with mHSPC showing ≥2 of 3 high-risk factors (Gleason score ≥8, ≥3 bone lesions or measurable visceral metastases) who received AAP plus ADT at our hospital between March 2018 and October 2019. We compared outcomes between the propensity-score matched AAP plus ADT group and the combined androgen blockade (CAB) group (19 matched pairs, 38 patients) to evaluate the efficacy and safety of AAP plus ADT. Prostate-specific antigen progression-free survival (PSA-PFS) was significantly longer in the AAP group than in the CAB group (not reached vs 15.1 months, p=0.014). Time to achievement of serum PSA ≤0.2 ng/ml and ≤0.1 ng/ml was shorter in the AAP group than in the CAB group (6.4 months vs not reached, p=0.001 and 11.0 months vs not reached, p=0.004, respectively). Although no significant intergroup difference was observed in the overall survival rates and PSA-PFS2 (PSAPFS on subsequent anticancer therapy) owing to the shorter follow-up in the AAP group, our data suggest that the clinical efficacy of AAP is betterthan that of CAB in patients with mHSPC.

Incomplete Complement Inhibition in Patients with PNH on Eculizumab - 5 Year Experience from the National PNH Service Leeds

Background Paroxysmal Nocturnal Hemoglobinuria (PNH) is a rare acquired disorder characterised by intravascular hemolysis and thrombosis. Patients with symptomatic PNH are commenced on the complement inhibitor eculizumab (600mg weekly for 5 weeks then 900mg 2 weekly). This monoclonal antibody targets C5 in the complement cascade, halting terminal complement activation thus inhibiting intravascular hemolysis. In some patients intravascular hemolysis is not adequately controlled on the standard regimen. Patient symptoms, transfusion requirements and raised Lactate dehydrogenase (LDH) levels are indicators for suboptimal control of PNH and review of eculizumab dosing. The 50% hemolytic complement (CH50) test is a functional assay assessing capability of serum complement components of the classical pathway to lyse sheep red blood cells pre-coated with rabbit anti-sheep red blood cell antibody. Patients with complement inhibited PNH should demonstrate absent lysis. As the test is expensive and difficult to organise, we tested if incomplete complete blockade as determined by CH50 activity would be better to confirm under-dosing than LDH value. Methods The Leeds (UK) PNH National Service reviewed patients who underwent CH50 assay between January 2015 and March 2020. All patients were on eculizumab with clinical concerns regarding suboptimal control of PNH. Patients receive eculizumab infusions intravenously every 14 days and routine follow up from the PNH Service. Serum samples were obtained 24 hours prior to infusions for CH50 assay; LDH values were routinely collected. Complete complement blockade was defined by &amp;lt;10% CH50 activity; intravascular hemolysis was indicated by LDH value &amp;gt;1.5x upper limit of normal (ULN). Confidence intervals were set at 95% and significance set at p&amp;lt;0.05. Results In the study period, 327 tests (median 2, range 1 - 8) were carried out in 146 patients (median age 54 years, range 16 - 89; 74 female). 81% (265) were successful; 19% (62) were unsuccessful due to processing errors. Of the successful tests, 74% (197 in 127 patients) indicated complete complement blockade and 26% (68 in 38 patients) indicated incomplete blockade. Of the patients with incomplete blockade, 68% (26) demonstrated complete blockade on repeat testing and 32% (12) had their eculizumab dose increased. Clinical symptoms of under-dosing in the 12 patients requiring a dose increase included increased transfusion requirements and/or breakthrough hemolysis (7), pregnancy (2; both returned to 900mg post pregnancy) and significant lethargy (3). Of the patients requiring a dose increase, 3 were on 1200mg before 2015; their dose was increased to 1500mg. Repeat testing was carried out in 10/12 patients after dose increase; 8 indicated complete blockade; 2 patients were incompletely blocked at 1200mg and received a further dose increase to 1500mg. Further testing indicated complete blockade in 1 patient; 1 required a 3rd dose increase to 1800mg due to incomplete blockade and ongoing transfusion requirement. Corresponding LDH values were analysed; median LDH for the complete blockade group was 1.16xULN (range 0.54 - 2.16) and 1.28xULN (range 0.76 - 2.38) for the incomplete blockade group. LDH values were not significantly higher in the incomplete blockade group compared to the complete blockade group, p=0.08. There was no significant difference in LDH values pre- and post-dose increase, p=0.38 (Figure 1); median pre-dose increase LDH 1.14xULN; median post-dose increase LDH 1.13xULN. Correlation coefficient shows that CH50 activity was positively correlated with LDH value, r(123)=0.18, p=0.04. Conclusion We report the effective utilisation of CH50 analysis where there is clinical concern of suboptimal control of PNH. All patients demonstrating hemolytic activity on CH50 assays indicated subsequent complement blockade following increase of eculizumab dose. Increasing eculizumab is costly requiring robust evidence of suboptimal complement inhibition; a positive correlation between CH50 activity and LDH values was shown however this is not sufficient to guide clinical decisions. LDH values of the incomplete blockade group were not significantly higher than those with complete blockade, suggesting the use of LDH values as an assessment of complement inhibition in patients with ongoing symptoms or transfusion requirements is not sufficient to guide eculizumab dose increases. Disclosures Munir: Alexion: Honoraria; F. Hoffmann-La Roche: Consultancy, Other: Medical writing support, furnished by Scott Battle, PhD, of Health Interactions, was funded by F. Hoffmann-La Roche Ltd, Basel, Switzerland. Pike:Apellis: Research Funding. Arnold:Alexion Pharmaceuticals: Honoraria. Hillmen:AstraZeneca: Consultancy, Speakers Bureau; Alexion: Consultancy, Research Funding, Speakers Bureau; Acerta: Other: Financial or material support; Roche: Consultancy, Other: Financial or material support, Research Funding, Speakers Bureau; AbbVie: Consultancy, Other: Financial or material support, Research Funding, Speakers Bureau; Pharmacyclics: Other: Financial or material support, Research Funding; Janssen: Consultancy, Other: Financial or material support, Research Funding, Speakers Bureau; Apellis: Consultancy, Research Funding, Speakers Bureau; Gilead: Other: Financial or material support, Research Funding. Griffin:Alexion Pharmaceuticals: Honoraria, Other: Conference Support; Biocryst: Membership on an entity's Board of Directors or advisory committees.

Renin-Angiotensin System Blockade in Aortic Stenosis: Implications Before and After Aortic Valve Replacement.

Aortic stenosis (AS) is a common valvular heart disease in the aging population that is characterized by a variable period of asymptomatic phase before development of symptoms and severe AS. Mortality and morbidity is substantial even after aortic valve replacement, in part related to persistent left ventricular hypertrophy, diastolic dysfunction, and heart failure. Renin‐angiotensin system (RAS) blockade therapy is associated with modulation of adverse left ventricular remodeling, reduction in myocardial hypertrophy, and fibrosis, resulting in clinical improvements in patients with congestive heart failure There are emerging data to suggest benefit of RAS blockade in patients with AS before and after AVR with regard to potentially slower progression of aortic valve calcification, left ventricular mass and survival benefit in favor of RAS blockade group before AVR, and also survival benefit in patients after AVR. We review the available data to understand the role of RAS blockade before AVR and in patients undergoing surgical AVR and transcatheter AVR. There are significant survival advantages of RAS inhibition in patients with AS undergoing surgical AVR or transcatheter AVR. On the basis of existing literature, adequately powered randomized trials are needed to evaluate the role of RAS inhibition in patients with AS.

Femoral nerve catheters and limb strength asymmetry at 6 months after primary anterior cruciate ligament reconstruction in pediatric patients.

The postoperative implications of single-injection femoral nerve blockade and femoral nerve catheter placement for anterior cruciate ligament reconstruction are not well defined among pediatric patients. Femoral nerve blockade may be associated with deficits in quadriceps symmetry at 6months postoperative. We compared outcomes after primary anterior cruciate ligament reconstruction surgery in pediatric patients who received either a single-injection femoral nerve block or femoral nerve catheter and a single-injection popliteal nerve block. We conducted a retrospective chart review of patients 10-19years of age who underwent anterior cruciate ligament reconstruction with quadriceps tendon-patellar bone autograft by a single orthopedic surgeon at two of our locations. Of 88 patients analyzed, 31 received single-injection femoral nerve blockade (52% female, mean age=15.6±1.8years) and 57 received femoral nerve catheter (53% female, mean age=15.6±1.7years). Time from surgery to return-to-sport clearance and movement symmetry were compared between groups at approximately 6months postoperatively. The single-injection femoral nerve blockade group exhibited significantly greater single-leg squat symmetry than did the femoral nerve catheter group (95.5±6.7% vs 88.3±9.3%; P= 0.02; mean difference=7.2%, 95% CI=-1.1, 13.3) 6months postoperatively. There was no difference in time from surgery to return-to-sport clearance between groups (median=247 [interquartile range=218-295] days vs 268 [241-331] days; P= 0.22; mean difference=40days; 95% CI=-23, 102). Though time to return to sport did not differ, patients in the femoral nerve catheter group exhibited greater single-leg squat asymmetry than did those in the femoral nerve blockade group approximately 6months postoperatively. Persistent functional deficits may be important to consider when treating pediatric patients undergoing anterior cruciate ligament reconstruction.

Single versus dual blockade of the renin-angiotensin system in patients with IgA nephropathy

BackgroundInhibitors of the renin-angiotensin system (RAS) are cornerstones of supportive therapy in patients with IgA nephropathy (IgAN). We analyzed the effects of single versus dual RAS blockaQueryde during our randomized STOP-IgAN trial.MethodsSTOP-IgAN participants with available successive information on their RAS treatment regimen and renal outcomes during the randomized 3-year trial phase were stratified post hoc into two groups, i.e. patients under continuous single or dual RAS blocker therapy over the entire 3 years of the trial phase. Primary and secondary STOP-IgAN trial endpoints, i.e. frequencies of full clinical remission, eGFR-loss ≥ 15 and ≥ 30 ml/min/1.73 m2 and ESRD onset, were analyzed by logistic regression and linear mixed effects models.ResultsAmong the 112 patients included in the present analysis, 82 (73%) were maintained on single and 30 (27%) on dual RAS inhibitor therapy throughout the trial. Neither RAS blocker strategy significantly affected full clinical remission, eGFR-loss rates, onset of ESRD. Proteinuria moderately increased in patients under dual RAS blockade by 0.1 g/g creatinine during the 3-year trial phase. This was particularly evident in patients without additional immunosuppression during the randomized trial phase, where proteinuria increased by 0.2 g/g creatinine in the dual RAS blockade group. In contrast, proteinuria decreased in patients under single RAS blocker therapy by 0.3 g/g creatinine. The course of eGFR remained stable and did not differ between the RAS treatment strategies.ConclusionIn the STOP-IgAN cohort, neither RAS blocker regimen altered renal outcomes. Patients on dual RAS blockade even exhibited higher proteinuria over the 3-year trial phase.

The effect of blocking penile blood drainage on stem cells therapy for rats with erectile dysfunction

Objective: To investigate the effect of blocking penile blood drainage at the root of the rat penis on cell retention, penile erectile function, and histopathological changes when erectile dysfunction (ED) is treated by intracavernous injection (ICI) of stem cells. Methods: Thirty male SD rats were randomly divided into sham operation group (n=6), ED model group (n=6), treatment group A (blockade group, n=9) and treatment group B (non-blockade group, n=9). Twenty-four hours after the model was established, group A and group B were treated by ICI of 1 × 10(6) adipose-derived stem cells (ADSCs). Before ICI, the penile blood drainage in group A was temporarily blocked with a rubber tourniquet at the root of the penis which was removed 5 minutes after the injection. The dynamic changes of the local fluorescent signal of the penis and the expression of the fluorescent signal in the lung were detected after ICI. The maximum intracavernous pressure/mean arterial pressure (ICPmax/MAP) was measured to evaluatethe erectile function, and histopathological changes of the penis were observed after 28 days. Results: At different time points (0, 10 and 60 min), the intensity of the bioluminescent signal (×10(6)·p·s(-1)·sr·cm(-2)) in group A had a similar trend when compared with that in group B, and the differences were not statistically significant (8.76±1.17 vs 8.16±1.12, 6.45±1.47 vs 6.72±0.69, 3.77±0.30 vs 3.36±1.06, all P>0.05). A large number of ADSCs could be found in the lungs in both treatment groups after 60 min of ICI. There was no statistically significant difference in erectile function (0.44±0.11 vs 0.43±0.07) and histopathological change (0.08±0.02 vs 0.08±0.03) regardless of the occlusion of blood drainage at the root of the penis (all P>0.05). Conclusion: Temporarily blocking of penile blood drainage has no obvious advantage in improving cell retention and efficacy when ADSCs are used to treat ED of rat models.

Protective effect of dexmedetomidine infusion combined with epidural blockade on postoperative complications after surgery: A prospective randomized controlled clinical trial.

ObjectivesThis prospective, randomized, controlled study aimed to explore the efficacy of dexmedetomidine combined with epidural blockade on postoperative recovery of elderly patients after radical resection for colorectal cancer.MethodsNinety-six elderly patients who underwent radical resection for colorectal cancer were randomly divided into the following four groups: dexmedetomidine, epidural blockade (ropivacaine), combined (dexmedetomidine + epidural blockade), and control (0.9% saline). The Mini-Mental State Examination (MMSE), Visual Analog Scale (VAS), and Ramsay scores at 48 hours, and time to first activity, length of hospital stay, and postoperative complication rates at 3 months were assessed.ResultsTwelve hours after surgery, Ramsay scores were higher in the combined compared with the control and epidural blockade groups. Twenty-four hours after surgery, MMSE scores were higher in the combined compared with the other groups. The combined group showed the lowest VAS scores except at 48 hours. Time to first activity and length of hospital stay were significantly shorter in the combined compared with the other groups. There was no difference in total postoperative complication rates among the groups.ConclusionsA combination of intraoperative dexmedetomidine infusion and epidural blockade could mitigate pain after surgery, improve cognitive dysfunction in early surgery, and facilitate recovery.