High-dose Bolus Research Articles

Effects of High Dose Bolus Cholecalciferol on Free Vitamin D Metabolites, Bone Turnover Markers and Physical Function.

High dose bolus cholecalciferol supplementation has been associated with falls and fracture, and this does not appear to be due to hypercalcaemia. The primary aim of this study was to determine the change in free vitamin D and metabolites after high dose bolus supplementation. This was a single centre, double-blinded, randomised, controlled trial of three different oral bolus doses of vitamin D3 (50,000 IU, 150,000 IU, and 500,000 IU) in otherwise healthy, vitamin D deficient (total 25-hydroxylated vitamin 25(OH)D < 30 nmol/L) postmenopausal women. Thirty-three women were randomized to one of the three treatment groups. Twenty-seven vitamin D sufficient (25(OH)D > 50 nmol/L) postmenopausal women were recruited as a concurrent control group. Participants attended five study visits over three months. We measured total 25(OH)D3 and free 25(OH)D, total and free 1,25(OH)2D, parathyroid hormone, fibroblast-growth factor-23, serum calcium, ionised calcium, urinary calcium excretion, and bone turnover markers (procollagen I N-propeptide (PINP), serum C-telopeptides of type I collagen (CTX-I) and Osteocalcin (OC)). We assessed muscle strength and function with grip strength and a short physical performance battery. Postural blood pressure and aldosterone:renin ratio (ARR) was also measured. Total 25(OH)D3 and free 25(OH)D increased in response to dose, and there were proportionate increases in total and free metabolites. Treatment did not affect serum calcium, postural blood pressure, ARR, or physical function. Bone turnover markers increased transiently one week after administration of 500,000 IU. High dose bolus cholecalciferol supplementation does not cause disproportionate increases in free vitamin D or metabolites. We did not identify any effect on blood pressure regulation or physical function that would explain increased falls after high dose treatment. A transient increase in bone turnover markers one week after a 500,000 IU bolus suggests that very high doses can have acute effects on bone metabolism, but the clinical significance of this transient increase is uncertain.

High dose bolus (HDB) interleukin-2 (IL2) and concurrent low dose ipilimumab followed sequentially by nivolumab in patients with advanced melanoma after failure of anti-PD1-based immunotherapy and BRAF-MEK inhibition.

9543 Background: Options are limited for patients with advanced metastatic melanoma who have disease progression following anti-PD1-based immunotherapy and BRAF-MEK inhibition (if BRAF V600 mutant). Evidence supports synergism between IL2 and CTLA4 blockade in enhancing the immunogenicity of the tumor microenvironment and therapeutic susceptibility to PD1 blockade. Methods: We conducted a phase II study of HDB IL2 in combination with LD ipilimumab followed sequentially by nivolumab in patients with advanced inoperable stage III or stage IV melanoma with progression after anti-PD1-based immunotherapy and BRAF-MEK inhibitors. Treatment consisted of up to 3 courses (One cycle is 21 days and one course is 4 cycles). HDB IL2 and concurrent ipilimumab 1 mg/kg were given during week 1 of the initial 2 cycles of each course. Nivolumab was given during week one of the 3rd cycle of each course. Patients without evidence of disease progression (RECIST v.1.1) or limiting toxicities (CTCAE v.5) were offered additional courses of treatment. A Simon two-stage minimax design (Simon, 1989) was followed. We report the outcomes for Stage I. Results: 12 pts (5 female, 7 male) with metastatic melanoma (2M1a, 1M1b, 6M1c, 3M1d) were treated. Median age 53 years (33 – 69), 11 cutaneous (including 1 acral) and 1 mucosal primary. Tumor mutation status: 4BRAF (V600E), 2NRAS (p.Q61K), 1NF1. The median number of prior regimens for metastatic melanoma was 3 (range 1 - 5). Eight patients previously received ipilimumab as monotherapy or in combination with anti-PD1. On study, the median number of doses of IL2 was 9 during cycle 1 and 7 during cycle 2. A median of 2 doses of ipilimumab and 1 dose of nivolumab were given as part of the combination regimen. Among the 11 evaluable patients (completed 1 course of systemic therapy), the response rate was 2/11 (18.2 %; 95% CI: 2.3% – 51.8%); 1CR, 1 PR, 5 SD, 4 PD and 1 NE as best response. After a median follow up of 39 months, both responses are ongoing (at 10+ and 37+ months), median progression free survival (PFS) was 3 months and median overall survival (OS) was 18.8 months. One-year PFS and OS were 17% (95% CI: 4.7% - 59%) and 83% (95% CI: 65% - 100%), respectively. The adverse event profile was consistent with the expected toxicity profile for each agent with no increase in frequency with the combination. Conclusions: Our combination regimen was relatively safe and well tolerated and demonstrated promising efficacy in a heavily pretreated patient population passing the prespecified efficacy criteria for Simon Stage I. The study has moved into Stage II testing. Clinical trial information: NCT04562129 .

Assessment of Swallowing Function in Patients with Head and Neck Squamous Cell Carcinoma in High vs. Low Dose Cisplatin

Cisplatin-based therapies are standard-of-care for advanced-stage head and neck squamous cell carcinoma (HNSCC). Treatment regimens include 3 weeks of high-dose bolus cisplatin or 6–7 weeks of low-dose weekly cisplatin, both with concurrent radiation. The effects of cisplatin dosage on swallowing function warrant further study. A 237-patient cohort treated for HNSCC at a single center were studied retrospectively. Gastrostomy tube dependence served as the primary endpoint. Secondary endpoints included weight changes, esophageal stricture, and lymphedema. The primary/secondary outcomes were not statistically significant; however, ototoxicity and renal toxicity were significantly higher in the high-dose group. These findings add insight into cisplatin dose-based functional outcomes.

A Randomized, Double-Blind, Graded Dose-Response Study of Norepinephrine Administration for Prevention of Post-Spinal Hypotension during Elective Cesarean Delivery.

Norepinephrine has been recently introduced for prophylaxis against post-spinal hypotension during cesarean delivery; however, no data are available regarding its optimum dosing scheme. The primary objective of this study is to compare three different infusion and bolus dose combinations of norepinephrine for prophylaxis against post-spinal hypotension during cesarean delivery. This randomized, double-blind study was performed between February 2021 and May 2022. The study protocol was registered at Clinicaltrials.gov with the identification number NCT04701190. A total of 192 parturients were enrolled into this study. Patients were assigned to three groups-Zero-Bolus High-Infusion (Group ZBHI, 0 µg/0.1 µg kg-1 min-1, n = 61), Moderate-Bolus Moderate-Infusion (Group MBMI, 5 µg/0.075 µg kg-1 min-1, n = 61) and High-Bolus Low-Infusion (Group HBLI, 10 µg/0.05 µg kg-1 min-1, n = 61)-according to different combinations of norepinephrine infusion and bolus doses. All patients received spinal anesthesia with 10 mg hyperbaric bupivacaine plus 12.5 µg fentanyl. Immediately after cerebrospinal fluid was obtained, patients underwent a norepinephrine protocol corresponding to the randomized group. The primary outcome was the incidence of post-spinal hypotension. Secondary outcomes were post-delivery hypotension, frequency of post-spinal hypertension and bradycardia, and neonatal outcomes. The incidence of post-spinal hypotension was 11.7% in Group HBLI, 6.7% in Group ZBHI and 1.7% in Group MBMI (p = 0.1). The overall incidence of post-delivery hypotension in parturients was 41.1% (p = 0.797). The lowest frequency of post-spinal bradycardia (8.3%) and hypertension (11.7%) was seen in Group HBLI. The neonatal APGAR scores at 1st minute were higher in Group MBMI than in Group ZBHI (8.58 vs. 8.23, p = 0.001). All three infusion and bolus dose combinations of norepinephrine effectively reduced the incidence of post-spinal hypotension. However, high-dose bolus (10 µg) followed by low-dose infusion (0.05 µg kg-1 min-1) of norepinephrine can be preferred due to the reduced frequency of bradycardia and hypertension during cesarean delivery under spinal anesthesia.

High-Dose Nitroglycerin Bolus and Non-Invasive Ventilation Prevent Intubation or ICU Admission on Hypertensive Emergency and Acute Pulmonary Edema: Sympathetic Crashing Acute Pulmonary Edema (SCAPE) Treatment on STEMI Patient: A Case Report

Highlight: 1. SCAPE could lead to respiratory failure when not treated promptly. 2. High-dose NTG and NIV support can be used as an alternative treatment to overcome hypertensive emergency and pulmonary edema, thus preventing the need for endotracheal intubation and ICU admission. - Background: A marked elevation in blood pressure that causes acute heart failure and fluid accumulation in the lungs is known as sympathetic crashing acute pulmonary edema (SCAPE). Here, we present a SCAPE patient with severe respiratory failure who was successfully treated with high-dose nitroglycerin (NTG) bolus and non-invasive ventilation (NIV). Case summary: A 48-year-old male was referred to our center with typical chest pain and dyspnea. Physical and additional examination found hypertensive emergency (196/66 mmHg), acute pulmonary edema, and acute heart failure, accompanied by anterior STEMI and severe respiratory failure (P/F ratio of 72) in need of intubation. He was given 2 mg intravenous NTG bolus twice supported with NIV, diuretics followed by the primary percutaneous coronary intervention (PCI) stenting in mid left anterior descending (LAD). The patient recovered from acute pulmonary edema, and the P/F ratio improved from 72 to 321 without intubation. Discussion: SCAPE could lead to respiratory failure requiring intubation and intensive care unit (ICU) admission when not treated promptly. The administration of large doses of NTG and NIV was safe and resulted in a speedy improvement in symptoms. Conclusion: SCAPE can be resolved without invasive procedures, using high-dose NTG and NIV support to overcome hypertensive emergency and pulmonary edema.

Platelet glycoprotein IIb/IIIa inhibitor tirofiban in clopidogrel-naïve patients undergoing elective percutaneous coronary intervention.

The safety of administration of tirofiban, aplatelet glycoprotein IIb/IIIa inhibitor, followed by aclopidogrel loading dose in clopidogrel-naïve patients undergoing ad-hoc percutaneous coronary intervention (PCI) is not yet clear. In aretrospective observational cohort analysis, clopidogrel-naïve patients undergoing ad-hoc PCI who received ahigh-dose bolus of tirofiban (25 μg/kg) followed by a600-mg clopidogrel loading dose (group1) were compared with patients undergoing elective PCI who were pretreated with clopidogrel (group2), between September 2014 and October 2021. The primary outcome was major adverse cardiovascular events (MACE) defined as the composite of death, myocardial infarction, stroke, target-lesion revascularisation and bleeding at 30days. Secondary outcomes were MACE at 7days and individual components of the primary outcome at 7and 30days. Atotal of 1404 patients were included: 432 (31%) in group1 and 972 (69%) in group2. Median age was 69years, and 28% were female. At 7‑day follow-up, MACE occurred in 1.4% in group1 versus 3.0% in group2 (p = 0.08). 30-day MACE were observed in 1.9% in group1 and 4.2% in group2 (p = 0.03). Secondary outcomes were comparable between the groups. Cox regression analysis, corrected for baseline differences, revealed no significant difference in the primary outcome (hazard ratio:1.8; 95% confidence interval: 0.8-3.9). Ad-hoc PCI in clopidogrel-naïve patients who were treated with high-dose bolus of tirofiban followed by aclopidogrel loading dose immediately after the procedure appeared to be safe.

Pioglitazone, a PPAR-y agonist, as one of the new therapeutic candidates for C3 glomerulopathy

BackgroundC3-glomerulopathy (C3G) is a rare pediatric kidney disease characterised by dysregulation of the alternative complement pathway, with glomerular deposition of C3. C3G may often present as a steroid-resistant nephrotic syndrome (SRNS), and there is no established effective therapy: the usual treatment involves corticosteroids and immunosuppressive drugs. Pioglitazone, a PPAR-γ agonist with a protective action on podocytes, was reported in a few cases as helpful in reducing proteinuria when combined with steroids.Case-Diagnosis/TreatmentWe report the case of a 13-year-old girl with silent past medical history who presented with SRNS. A kidney biopsy showed findings indicative of C3G. A low sodium diet and angiotensin-converting enzyme inhibitor were started; immunosuppressive treatment with mycophenolate mofetil (MMF) was administered due to the cortico-resistance. Because of poor response to the immunosuppressant, a trial with eculizumab was attempted without significant response and persistence of proteinuria in the nephrotic range. A further therapeutic trial was performed with tacrolimus with no disease remission. Due to a severe deterioration in her condition, the girl was hospitalized and treated with high-dose steroid bolus. A daily dose of oral prednisone and MMF were re-started without benefit with persistent levels of nephrotic range proteinuria. The administration of pioglitazone consistently lowered proteinuria levels for the first time since the onset of the disease, with a maintenance of the effect and normalization (< 0.15 g/24 h) at the 10-month follow-up.ConclusionsIn this patient affected by C3G, pioglitazone proved effective in reducing proteinuria levels.

A Mouse Model of Dilated Cardiomyopathy Produced by Isoproterenol Acute Exposure Followed by 5-Fluorouracil Administration.

Appropriate dilated cardiomyopathy (DCM) animal models are highly desirable considering the pathophysiological and clinical heterogeneity of DCM. Genetically modified mice are the most widely and intensively utilized research animals for DCM. However, to translate discoveries from basic science into new and personalized medical applications, research in non-genetically based DCM models remains a key issue. Here, we characterized a mouse model of non-ischemic DCM induced by a stepwise pharmacologic regime of Isoproterenol (ISO) high dose bolus followed by a low dose systemic injection of the chemotherapy agent, 5-Fluorouracil (5-FU). C57BL/6J mice were injected with ISO and, 3 days after, were randomly assigned to saline or 5-FU. Echocardiography and a strain analysis show that ISO + 5FU in mice induces progressive left ventricular (LV) dilation and reduced systolic function, along with diastolic dysfunction and a persistent global cardiac contractility depression through 56 days. While mice treated with ISO alone recover anatomically and functionally, ISO + 5-FU causes persistent cardiomyocyte death, ensuing in cardiomyocyte hypertrophy through 56 days. ISO + 5-FU-dependent damage was accompanied by significant myocardial disarray and fibrosis along with exaggerated oxidative stress, tissue inflammation and premature cell senescence accumulation. In conclusions, a combination of ISO + 5FU produces anatomical, histological and functional cardiac alterations typical of DCM, representing a widely available, affordable, and reproducible mouse model of this cardiomyopathy.

Acute effects of intravenous DMT in a randomized placebo-controlled study in healthy participants

N,N-dimethyltryptamine (DMT) is distinct among classic serotonergic psychedelics because of its short-lasting effects when administered intravenously. Despite growing interest in the experimental and therapeutic use of intravenous DMT, data are lacking on its clinical pharmacology. We conducted a double-blind, randomized, placebo-controlled crossover trial in 27 healthy participants to test different intravenous DMT administration regimens: placebo, low infusion (0.6 mg/min), high infusion (1 mg/min), low bolus + low infusion (15 mg + 0.6 mg/min), and high bolus + high infusion (25 mg + 1 mg/min). Study sessions lasted for 5 h and were separated by at least 1 week. Participant’s lifetime use of psychedelics was ≤20 times. Outcome measures included subjective, autonomic, and adverse effects, pharmacokinetics of DMT, and plasma levels of brain-derived neurotropic factor (BDNF) and oxytocin. Low (15 mg) and high (25 mg) DMT bolus doses rapidly induced very intense psychedelic effects that peaked within 2 min. DMT infusions (0.6 or 1 mg/min) without a bolus induced slowly increasing and dose-dependent psychedelic effects that reached plateaus after 30 min. Both bolus doses produced more negative subjective effects and anxiety than infusions. After stopping the infusion, all drug effects rapidly decreased and completely subsided within 15 min, consistent with a short early plasma elimination half-life (t1/2α) of 5.0–5.8 min, followed by longer late elimination (t1/2β = 14–16 min) after 15–20 min. Subjective effects of DMT were stable from 30 to 90 min, despite further increasing plasma concentrations, thus indicating acute tolerance to continuous DMT administration. Intravenous DMT, particularly when administered as an infusion, is a promising tool for the controlled induction of a psychedelic state that can be tailored to the specific needs of patients and therapeutic sessions.Trial registration: ClinicalTrials.gov identifier: NCT04353024

Comparative urine metabolomics of mice treated with non-toxic and toxic oral doses of (-)-epigallocatechin-3-gallate.

The green tea polyphenol, (-)-epigallocatechin-3-gallate (EGCG), has been studied for its potential positive health effects, but human and animal model studies have reported potential toxicity at high oral bolus doses. This study used liquid chromatography-mass spectrometry-based metabolomics to compare the urinary EGCG metabolite profile after administration of a single non-toxic (100 mg kg-1) or toxic (750 mg kg-1) oral bolus dose to male C57BL6/J mice to better understand how EGCG metabolism varies with dose. EGCG metabolites, including methyl, glucuronide, sulfate, and glucoside conjugates, were tentatively identified based on their mass to charge (m/z) ratio and fragment ion patterns. Partial least squares discriminant analysis (PLS-DA) results showed clear separation of the urine metabolite profiles between treatment groups. The most differentiating metabolites in the negative and positive ion modes were provisionally identified as di-glucuronidated EGCG quinone and di-glucuronidated EGCG, respectively. The presence of EGCG oxidation products at toxic dose is consistent with studies showing that EGCG toxicity is associated with oxidative stress. Relative amounts of methylated metabolites increased with dose to a lesser extent than glucuronide and sulfate metabolites, indicating that methylation is more prominent at low doses, whereas glucuronidation and sulfation may be more important at higher doses. One limitation of the current work is that the lack of commercially-available EGCG metabolite standards prevented absolute metabolite quantification and identification. Despite this limitation, these findings provide a basis for better understanding the dose-dependent changes in EGCG metabolism and advance studies on how these differences may contribute to the toxicity of high doses of EGCG.

Comparison of Intracoronary and Intravenous Administration of High Dose Bolus Tirofiban in Patients of St Elevation Myocardial Infarction Undergoing Primary Percutaneous Coronary Intervention

Acute ST-elevation myocardial infarction (STEMI) is a condition in which transmural myocardial ischemia causes myocardial necrosis and is the leading cause of death. Objectives: To compare the efficacy of tirofiban bolus administration via percutaneous coronary intervention (PCI) and intravenous route (IV) in STEMI patients for restoration of myocardial perfusion. Methods: A retrospective cross-sectional study was conducted at Cardiology Department, Hayatabad Medical Complex, Peshawar, during 2021-22. The study comprised 168 STEMI patients divided into Group A and B (n=84), treated with tirofiban PCI and IV route, respectively. Results: Incidence of STEMI was three folds higher in males than females, and the mean age of the patients was 55 years. Smoking and obesity were the potential risk factors. Patients in Group A had a better clinical outcome and prognosis than Group B. In comparison to the IV treatment group (91.66%), the ST-segment resolution time was considerably lower (P&lt;0.05) in the PCI group (48.80%). In both groups, the observational parameters for TIMI flow grade, TIMI major and minor bleeding, MBG, and MACE were not-significantly different (P≥0.05), comprising percentages 94, 3.57, 9.52, 71.42, 5.95%, and 84.52, 2.38, 13.09, 75, 15.47%, respectively. In comparison to IV therapy group, the LVEF percentage in PCI group was statistically significant (P&lt;0.05) after 24 hours and 30 days (57, 63 and 52, 58%, respectively). Conclusions: It was concluded that STEMI patients treated with PCI tirofiban bolus had significantly greater (p&lt;0.05) recovery rates, left ventricular ejection fractions and better clinical outcomes than IV-treated group

PSAT173 Weekly Supplementation with Vitamin D3 reduces 1,25(OH)2 vitamin D3 Measured by Mass Spectrometry, and increases Fibroblast-like growth factor 23 (FGF23) in Individuals with and without Primary Hyperparathyroidism (PHPT)

Abstract Introduction Vitamin D deficiency is a very common condition, which has been associated with more severe presentations of PHPT. It has been suggested that the Vitamin D replacement improves this prognosis, but there are few data regarding its effect on mineral homeostasis. The aim of this research was to evaluate the effects of weekly Vitamin D supplementation on the mineral metabolism in this population.Material and methods: In this prospective case-control trial, we evaluated the effects of 14,000 IU/week of oral Vitamin D3, for 12 weeks, on albumin-adjusted total Calcium (TCa), Parathormone (PTH), 25 hydroxyvitamin D3 (25OHD), intact FGF23 and 1,25dihydroxyvitamin D3 (1,25(OH)2D), in addition to other biochemical markers. Volunteers with active PHPT (n=55) and paired controls (n=64) collected fasting blood samples before and after 12 weeks of the Vitamin D supplementation. 1,25(OH)2D was measured by liquid chromatography and mass spectrometry, and other hormones by commercial immunometric assays. P&amp;lt;0.05 was considered significant. Results At baseline there were no differences between groups regarding 25OHD, FGF23 and clearance of creatinine. As expected, the concentrations of TCa, PTH, 1,25(OH)2D were higher in the PHPT. After supplementation, TCa and PTH did not change despite the significant increase on 25OHD in both groups, more markedly in the controls (from 22.7±6.1 to 31.5±6.8 ng/mL in PHPT; and from 20.4±5.8 to 32.5±6.4 ng/mL in controls). FGF23 levels significantly increased after supplementation in both groups, more markedly in the PHPT. (from 47.9 ± 27.1 to 76.3 ± 33.3 pg/mL in PHPT and from 40.5 ± 13.9 to 59.8±19.8 pg/mL in controls). A significant reduction in the concentrations of 1,25(OH)2D was seen in both groups, (time effect p-value&amp;lt;0.001), with more intensity in the PHPT group (time x group effect p-value=0.015) (from 94.8±34.6 to 68.9±25.3 pg/mL in PHPT and from 68.7±23.5 to 56.4±20.7pg/mL in controls). The delta of 1,25(OH)2D was inversely correlated with the delta of FGF23 in both the PHPT (r=-0.302, p-value=0.028) and control (r=-0.278, p-value=0.027) groups. Conclusion In both patient groups (with and without PHPT), weekly administration of 14,000IU of Vitamin D3 reduced 1,25(OH)2D concentrations measured by mass spectrometry, probably due to the inhibition of 1α-hydroxylase induced by the increase in FGF23. This phenomenon could explain the absence of hypercalcemia after supplementation, even in individuals with active PHPT, appearing to be a protective mechanism against Vitamin D excess. Future studies are needed to see if this increase in FGF23 could explain the paradoxical effects observed with the high bolus doses of vitamin D described by others.*This research received public grants from FAPESP (Fundação de Amparo a Pesquisa do Estado de Sao Paulo), with technical support from Laboratorio Fleury Presentation: Saturday, June 11, 2022 1:00 p.m. - 3:00 p.m.

High-dose adenosine versus saline-induced cardioplegic arrest in coronary artery bypass grafting: A randomized double-blind clinical feasibility trial.

In this clinical trial, we evaluated if a short-acting nucleoside, adenosine, as a high-dose bolus injection with blood cardioplegia induces faster arrest and provides better myocardial performance in patients after bypass surgery for coronary artery disease. Forty-three patients scheduled for elective or urgent coronary artery bypass grafting were prospectively recruited in two-arm 1:1 randomized parallel groups to either receive 20 mg of adenosine (in 21 patients) or saline (in 22 patients) into the aortic root during the first potassium-enriched blood cardioplegia infusion. The main outcomes of the study were ventricular myocardial performance measured with cardiac index, right ventricular stroke work index, and left ventricular stroke work index at predefined time points and time to asystole after a single bolus injection of adenosine. Conventional myocardial biomarkers were compared between the two groups at predefined time points as secondary endpoints. Electrocardiographic data and other ad hoc clinical outcomes were compared between the groups. Compared with saline, adenosine reduced the time to asystole (68 (95% confidence interval (95% CI) = 37-100) versus 150 (95% CI = 100-210) seconds, p = 0.005). With myocardial performance, the results were inconclusive, since right ventricular stroke work index recovered better in the adenosine group (p = 0.008), but there were no significant overall differences in cardiac index and left ventricular stroke work index between the groups. Only the post-cardiopulmonary bypass cardiac index was better in the adenosine group (2.3 (95% CI = 2.2-2.5) versus 2.1 (95% CI = 1.9-2.2) L/min/m2, p = 0.016). There were no significant differences between the groups in cardiac biomarker values. A high dose adenosine bolus at the beginning of the first cardioplegia infusion resulted in significantly faster asystole in coronary artery bypass grafting patients but enhanced only partially the ventricular performance.EudraCT number: 2014-001382-26. https://www.clinicaltrialsregister.eu/ctr-search/trial/2014-001382-26/FI.

Treatment of Acute Spinal Cord Injuries: A Survey Among Iberolatinoamerican Spine Surgeons - Part 1: Use of High-Dose Corticosteroids.

Objective The aim of the present study was to evaluate the current practice of using of methylprednisolone sodium succinate (MPSS) in acute spinal cord Injuries (ASCIs) among spine surgeons from Iberolatinoamerican countries. Methods A descriptive cross-sectional study design as a survey was conducted. A questionnaire composed of 2 sections, one on demographic data regarding the surgeons and MPSS administration, was sent by email to members of the Sociedad Ibero Latinoamericana de Columna (SILACO, in the Spanish acronym) and associated societies. Results A total of 182 surgeons participated in the study: 65.4% (119) orthopedic surgeons and 24.6% (63) neurosurgeons. Sixty-nine (37.9%) used MPSS in the initial management of ASCIs. There were no significant differences between countries ( p = 0.451), specialty ( p = 0.352), or surgeon seniority ( p = 0.652) for the use of corticosteroids in the initial management of ASCIs. Forty-five (65.2%) respondents reported using an initial high-dose bolus (30 mg/Kg) followed by a perfusion (5.4 mg/kg/h). Forty-six (66.7%) surgeons who used MPSS only prescribed it if the patients presented within 8 hours of the ASCI. Most of the surgeons (50.7% [35]) administered high-dose corticosteroids because of the conviction that it has clinal benefits and improves neurological recovery. Conclusion Results from the present survey show that MPSS use in ASCI is not widespread within spine surgeons and that the controversy regarding its use remains unresolved. This is probably due to the low level of evidence of the available data, to variations over the years, to inconsistencies in acute care protocols, and to health service pathways.

Cutaneous reaction to ifosfamide plus mesna treated with desensitization challenge: a case report

BackgroundIfosfamide is an alkylating agent used in the treatment of a wide range of tumours. Because of known side effects it is usually administered in combination with mesna, a thiol agent with uroprotective activity, to reduce them and increase the therapeutic dose. The most frequently administered regimens for ifosfamide are fractionated doses for 3 to 5 days, high-dose intravenous bolus, and continuous infusion over 24 to 72 h. Hypersensitivity reactions to ifosfamide plus mesna are not frequently described in the literature. Moreover, no reports exist concerning desensitization for this chemotherapy combination.Case presentationA 47-year-old man with stage IV renal sarcoma was treated with the combination of ifosfamide and mesna every 3 weeks in a 4-consecutive-day infusion protocol. During the second cycle of chemotherapy, he presented acute cutaneous symptoms. A 12-step desensitization protocol was proposed in view of the lack of knowledge of the possible hypersensitivity reactions to this combination of chemotherapy agents, and the multiple difficulties found during the study of the case.ConclusionsThe 12-step desensitization protocol was well tolerated. Therefore, it is an appropriate and safe option in the case of suspected allergy to ifosfamide plus mesna.

Ondansetron as Prophylactic against Hypotension and Bradycardia Following Spinal Anaesthesia in Elective Caesarean Section: a Case Control Study

Introduction: Hypotension and bradycardia following the administration of spinal anesthesia for cesarean section are very common and bear profound detrimental effects both on mother and baby. In our country, a significant proportion of patients undergo cesarean section delivery. Considering the workload and the socio-economic condition it is often a bad headache for our anesthesiologists to combat post-spinal hypotension. Vasopressor drugs have been widely used to prevent and treat maternal hypotension during cesarean section under spinal anesthesia. A combination of preloading and using vasopressor has maximum efficacy in preventing spinal-induced hypotension but with compromising with some detrimental adverse effects of vasopressor. Amongst vasopressors, ephedrine is widely used but studies found that a higher bolus dose is often required to prevent hypotension and bradycardia. Aim of the study: To find out the efficacy of ondansetron to prevent haemodynamic derrangement in cesarean section under spinal anaesthesia. Methods: This Prospective Randomized Double-Blind Comparative study was conducted at the Department of Anesthesiology and ICU, Dhaka Medical College Hospital, Dhaka, Bangladesh. The study duration was ten months, from March 2015 to January 2016. A total of 120 participants were randomly included in this study.Each participant was included either into “Group A (n=60)” or “Group B (n=60)” by using fixed number card sampling as mentioned earlier. Group B had been considered as control group in the study, Participants of group A received intravenous ondansetron (0.1 mg/kg body weight) and group B received ephedrine (0.5 mg/kg body weight). Result: The majority of the participants (58.33%) from both groups were from the age group of 26-30 years. Parity distribution revealed that 59.17% (n=71) patients were multigravida while 40.33% (n=49) were primi. In total, 80.33% of the participants had ASA I physical status, and 19.17% had ASA II. All patients .......

P371 The addition of intravenous, high dose, bolus of methyl-prednisolone increases the early clinical response to oral corticosteroids in moderately active ulcerative colitis. Preliminary results of a prospective, controlled, multicentre, randomised, open-label study

Abstract Background Oral corticosteroids remain the treatment of choice for moderately active flares of ulcerative colitis (UC). In early controlled studies, oral corticosteroids achieved clinical remission rates of, 30–60% at, 30 days. Some small prospective studies observed that the administration of high-dose intravenous bolus of methyl-prednisolone accelerated their therapeutic action and increased the rate of clinical response. We aimed to evaluate if the outpatient administration of intravenous, high-dose, methyl-prednisolone bolus increases the efficacy of a conventional course of oral prednisone in moderately active UC. Methods Prospective, multicentre, controlled, randomized, open-label study comparing the therapeutic efficacy of a standard oral prednisone schedule with the same schedule preceded by a three-day regimen of high-dose intravenous bolus of methyl-prednisolone. Inclusion criteria were: Moderately active, left-sided/extensive UC (total Mayo score, 6–10), with no prior exposure to immunosuppressants or biologics, and no corticosteroid treatment in the last, 6 months. Patients were randomized to oral prednisone, 60mg/day (ORAL group) or the same schedule preceded by intravenous bolus of, 500mg of methyl-prednisolone for three consecutive days (BOLUS group), stratified by the baseline use of oral, 5ASA and UC onset. Early clinical response was defined as the reduction of the baseline partial Mayo Score (pMS) by at least three points with at least a decrease by, 1 point in rectal bleeding and with an absolute value of, 0 or, 1, seven days after starting treatment (EUDRA CT:, 2016-001170-15)(Clinicaltrials.gov: NCT02921555) Results In all, 71 patients (38 ORAL, 33 BOLUS) were included. At baseline, the median pMS was, 6 (IQR, 5–7). In, 21% of the patients, the index flare was the onset of UC and, 68% had never received systemic corticosteroids for UC. There were no differences in baseline clinical and demographic features between the two study groups. At day, 7, the proportion of patients fulfilling early clinical response criteria was similar in both groups (BOLUS, 63% vs. ORAL, 58%; p = 0.6), but a significantly greater reduction in pMS at day, 3 (-3.4. vs -1.7; p &amp;lt;0.0001) and a significantly higher proportion of patients in clinical remission (pMS &amp;lt;2) at day, 7 (57% vs, 29%; p = 0.017) were observed in the BOLUS group. Conclusion The addition of three high-dose intravenous bolus of methyl-prednisolone to a standard schedule of oral corticosteroids achieves a faster and more intense response in the short-term in moderately active flares of UC, but it does not increase the clinical response rate at seven days. The impact of these effects on the medium-term outcomes is still to be assessed.

Effect of Different Corticosteroid Regimens on the Outcome of Severe COVID-19-Related Acute Respiratory Failure. A Retrospective Analysis.

Background: Systemic corticosteroids are associated with reduced mortality in COVID-19-related acute respiratory failure; however, the type and dose has not yet been established. Objectives: To compare the outcomes of dexamethasone vs. methylprednisolone, along with the effects of rescue, short-term, high-dose boluses of corticosteroids. Methods: Before/after and case/control retrospective analysis of consecutive critically ill COVID-19 subjects. Subjects were initially given dexamethasone; however, after review of the local protocol, methylprednisolone was suggested. A three-day course of 1000 mg/day of methylprednisolone was administered in the case of refractory hypoxemia within the first 10 days of treatment. Propensity score-adjusted comparisons were performed. Results: A total of 81 consecutive subjects were included (85% males, 60 ± 10 years, SAPS II 27 ± 7, SOFA 4 [IQR 3, 6] points) and 51 of these subjects (62.9%) received dexamethasone and 29 (35.8%) had methylprednisolone. The groups were well matched for age, comorbidities, and severity at admission. No differences were found in the duration of ICU stay, hospital mortality, or infectious complications between the groups. A total of 22 subjects (27.2%) received a rescue bolus; these subjects had a significantly lower oxygenation, a higher driving pressure, and an increased ventilatory ratio during the first ten days. Short-term/high-dose boluses were associated with higher hospital mortality, longer mechanical ventilation and ICU and hospital stay, and more infectious complications. A subgroup of subjects who received the boluses had significantly improved oxygenation and lower hospital mortality. Conclusions: We were unable to find any difference between dexamethasone or methylprednisolone on the explored outcomes; high-dose boluses of corticosteroids were associated with a worse outcome. However, a subgroup of subjects was identified in whom the high-dose boluses seemed beneficial.

Management of Joint Replacement in Hemophilia a with Inhibitors during Emicizumab Prophylaxis

IntroductionEmicizumab is a humanized monoclonal antibody that showed high efficacy in preventing bleeds in patients with hemophilia A and inhibitors aged > 12 years (HAVEN 1 study, Oldenburg et al. NEJM 2017). Thrombotic microangiopathy and thrombosis were reported in patients who received multiple doses of >100 IU/kg activated prothrombin complex concentrate (aPCC) for breakthrough bleeds. The surgical setting represents a challenge in hemophilia management due to the risk of peri-operative bleeding especially in inhibitor patients in whom intensive by-passing therapy is usually required with unpredictable and sometimes suboptimal efficacy. Here we present the management of a major non-elective orthopaedic surgery performed in one patient enrolled in the HAVEN 1 study at our Institution.MethodsAs per protocol, the patient received emicizumab 3 mg/kg subcutaneously once weekly for the first 4 weeks followed by 1.5 mg/kg/week. During the trial, right hip replacement was required due to displacement of the screws used to fix a previous femoral fracture. He continued emicizumab prophylaxis throughout the peri- and post-operative period.Based on our practice and protocol recommendations, we chose recombinant FVIIa (rFVIIa) as the hemostatic by-passing agent to manage the surgical procedure. FVIII replacement was considered as alternative option in the presence of an inhibitor titer < 5 BU/mL. No tromboprophylaxis was given.Anti-FVIII inhibitors were measured by chromogenic assay using bovine substrates (Chromogenix, Coamatic® Factor VIII, IL) and therapeutic FVIII levels by chromogenic assay with human substrates (Biophen FVIII:C, Hyphen BioMed).Cell blood count, D-dimer, fibrinogen, LDH, haptoglobin and blood film were monitored peri- and post-operatively.Thrombin generation assay (Thrombinoscope™, Thrombinoscope BV) was performed on platelet-rich and platelet-poor plasma pre- and post-operatively.ResultsMedical history: the patient, aged 56 years, had high-responding inhibitors since childhood (peak titer: 126 BU/mL) and treated bleeds with aPCC, plasma-derived porcine FVIII and rFVIIa. He previously underwent femur fracture fixation and total knee replacement that were both managed with rFVIIa by continuous infusion and high-dose boluses (140-190 mcg/kg every 2 hours for the first 48h), respectively. Both procedures were complicated by severe bleeding (blood loss >1500 mL) and controlled by repeated high-dose rFVIIa boluses and sequential treatment with by-passing agents (alternate dosing of aPCC and rFVIIa), respectively.Surgical management during HAVEN 1 trial: rFVIIa 100 mcg/kg was administered pre-operatively. Surgery lasted 1,5h and was uneventful with an intraoperative blood loss of 650 mL (as expected). During Day 0 rFVIIa was continued at 80 mcg/kg every 3h and hemoglobin (Hb) level and platelet count dropped (Table 1). Schistocytes were never detected and haptoglobin always normal. On Day 1 a right thigh hematoma developed and Hb levels further dropped despite packed red blood cells transfusions. Inhibitor titer at that time was 2 BU/mL, therefore we chose FVIII therapy (Klott, Kedrion) to control bleeding rather than intensify rFVIIa regimen. He received 115 IU/kg by bolus followed by continuous infusion at 3.3-4 IU/kg/h. FVIII levels were maintained above 70 IU/dL until Day 7 when FVIII decreased to 24 IU/dL despite increasing FVIII infusion rate up to 6 IU/kg/h. Platelet count progressively improved during FVIII treatment. The patient was switched back to rFVIIa 80 mcg/kg every 4-8h in association with antifibrinolytic therapy until discharge on Day 13; in this period platelet count were in the normal range.Thrombin generation parameters were in the normal range during emicizumab prophylaxis as well as during the peri- and post-operative period.ConclusionIn this patient a low-dose rFVIIa regimen was used for hip replacement without thrombotic microangiopathy or thrombosis and it was not sufficient to prevent bleeding. Bleeding was controlled by FVIII therapy to avoid intensive rFVIIa treatment or other by-passing agents owing to the concern of thrombotic risk. FVIII replacement therapy in association with emicizumab was safe and effective under proper laboratory monitoring. In conclusion, major orthopaedic surgery in patients on emicizumab requires expert multidisciplinary team supported by specialized coagulation laboratory. [Display omitted] DisclosuresSantagostino:Bayer, Shire, Pfizer, Novo Nordisk, Kedrion, Roche, Sobi, Bioverativ: Other: Advisory board; : Bayer, Shire, Pfizer, Novo Nordisk, Kedrion, Roche, Sobi, Bioverativ, CSL Behring, Grifols, Octapharma: Speakers Bureau. Mancuso:Bayer, CSL Behring, Octapharma, Novo Nordisk, Sobi, Pfizer: Speakers Bureau; Novo Nordisk, Sobi, CSL Behring, Bayer: Membership on an entity's Board of Directors or advisory committees. Pasta:Pfizer, Novo Nordisk, Bayer: Speakers Bureau; Pfizer: Membership on an entity's Board of Directors or advisory committees. Solimeno:Baxalta/Shire, Novo Nordisk, Bayer, Pfizer: Speakers Bureau; Novo Nordisk: Membership on an entity's Board of Directors or advisory committees. Peyvandi:Ablynx, Roche: Membership on an entity's Board of Directors or advisory committees; Ablynx, Bayer, Grifols, Novo Nordisk, Sobi: Speakers Bureau; Freeline, Kedrion, LFB, Octapharma: Consultancy.

Adverse neural effects of delayed, intermittent treatment with rEPO after asphyxia in preterm fetal sheep.

We have previously shown that high-dose constant infusion of recombinant human erythropoietin (rEPO) from 30min to 72 h after asphyxia in preterm fetal sheep reduced histological injury and improved electrophysiological recovery. This study shows that a high-dose infusion of rEPO from 6 to 72h after asphyxia did not improve EEG recovery, oligodendrocyte and neuronal survival at 1week post-asphyxia. Of concern, intermittent rEPO boluses started 6h after asphyxia were associated with impaired EEG recovery and bilateral cystic injury of temporal lobe intragyral white matter. Intermittent boluses of rEPO were associated with significantly increased cerebral vascular resistance and hypoperfusion, particularly after the first dose, but did not affect seizures, suggesting mismatch between perfusion and brain activity. Recombinant human erythropoietin (rEPO) is a promising treatment for hypoxic-ischaemic brain injury. Disappointingly, a large randomized controlled trial in preterm infants found that prophylactic, repeated high-dose rEPO boluses started within 24h of birth did not improve neurodevelopmental outcomes. We examined whether initiation of a continuous infusion of rEPO at the end of the latent phase after hypoxic-ischaemia (HI) might improve outcomes compared with intermittent bolus injections. Chronically instrumented preterm (0.7 gestation) fetal sheep received sham asphyxia or asphyxia induced by complete umbilical cord occlusion for 25min. Six hours after asphyxia, fetuses received either a continuous infusion of rEPO (loading dose 2000IU, infusion at 520IU/h) from 6 to 72h post-asphyxia or intravenous saline or 5000IU rEPO, with repeated doses every 48h for 5days. Continuous infusion of rEPO did not improve EEG recovery, oligodendrocyte and neuronal survival at 1week post-asphyxia. By contrast, intermittent rEPO boluses were associated with impaired EEG recovery and bilateral cystic injury of temporal lobe intragyral white matter in 6/8 fetuses. These studies demonstrate for the first time that initiation of intermittent rEPO boluses 6h after HI, at a dose comparable with recent clinical trials, exacerbated neural injury. These data reinforce the importance of early initiation of many potential neuroprotective therapies.