Slow Infusion Research Articles

PS-C20-5: WARM IV INFUSION IN HYPERTENSIVE URGENCY

Background: Hypertensive Urgency is defined as marked elevation in systemic blood pressure without any evidence of end organ damage. At present, the condition is managed with intravenous (IV) antihypertensives, of which most common is Sodium Nitroprusside. Aim: In this abstract we explore the possibility of slow IV infusion of warm (37–38oC) Normal Saline along with IV antihypertensives for a better and faster management of Hypertensive Urgency. Content: The slow IV will gradually increase the core body temperature of the patient while preventing fluid overload. Homeostatic regulation of Systemic Blood Pressure is maintained by an intricate network of correlated mechanisms, most of which are temperature dependent. The raised body temperature will be useful to control the Blood Pressure through the following mechanisms - Cardiac Output: reduces as core body temperature increases. Baroreflex: decreased post-synaptic adrenergic vasoconstrictor responses. Chemoreceptors: vascular responsiveness to adrenergic receptor stimulation reduces at higher temperatures. RAAS: Kosunen et al recorded reduced Systolic and Diastolic Blood Pressures at raised body temperatures despite increased levels of Angiotensin II & Aldosterone. Endothelin: Serum concentration of Endothelin-I reduces at higher temperatures. Sweat: Thermal stimulation of sweat gland will help excretion of both salt and water, thus maintaining the sodium balance. VEGF: VEGF-A, a potent vasodilator, is increased during elevated body temperature. However, apart from Blood Pressure, a change in core body temperature causes change in many other parameters as well, which must be considered during this discussion. Coagulation profile - Valeri et al noted no change in in-vivo coagulation states till 100oF Effect on other visceral organs - Internal visceral organs like Liver, Kidneys and Brain were not affected till 100oF Infection Control - Core body temperature close to 100oF has also been found to have a protective role against invasive fungal infections in the ICU Discussion: Though the effects of various antihypertensive drugs to raised body temperatures need to be tested, the above points prove that introducing a protocol of warm IV saline Infusion in patients of Hypertensive Urgency may be extremely beneficial, and also prevent clinical inertia.

The effects of antifibrinolytic drug use in decreasing hemoglobin drop following Percutaneous Nephrolithotomy in Al-Hillah Province

Introduction: Objective: To assess the effectiveness and safety of tranexamic acid in lowering postoperative haemoglobin and hematocrit decline, operational time, postoperative complications, and hospitalisation in percutaneous nephrolithotomy patients. Methods: A 40-patient Al-Hilla Teaching Hospital randomised controlled clinical trial ran from January 2020 through July 2022. All ultrasound-guided PCNL patients with renal stones were randomised into two groups. Group A consisted of 20 patients (13 males and 7 females) with a mean age of (45.05 ±12.23) years who received tranexamic acid (1gm slow intravenous infusion diluted in 100 cc normal saline over 10 minutes) on call to surgery and then (0.5 gm infusion every 8 hours for the first 24 hours postoperatively). Group B included 20 non-tranexamic acid-treated patients (9 males and 11 females) with a mean age of 42.15 ± 10.64 years. We are comparing haemoglobin and hematocrit decline, operational time, postoperative complications, and hospitalisation between two groups. Results: Group A had a much lower postoperative haemoglobin decline than group B, 12.97 ±1.21 g/dl vs 11.82 ±1.44 (p = 0.010). Group A had a much lower postoperative hematocrit decline (39.11 ±3.95%) than group B (34.86 ±3.73%) (p = 0.001). 63.25 ±10.79 minutes against 73.50 ±16.31 minutes (p = 0.024). Group A had a significantly shorter hospital stay than group B (54.00 ±10.66 hours vs. 60.60 ±11.74 hours, p = 0.021). All patients in two groups had postoperative moderate hematuria, however group B had 4 (20.0%) instances of severe hematuria, whereas group A had just one (5%) case (p = 0.047). Four (20.0%) group B patients and one (5%) group A case required blood transfusion, a statistically significant difference (p = 0.047). Conclusions: TXA reduces postoperative haemoglobin and hematocrit drops and blood transfusions in PCNL with minimal side effects and a shorter operational time and hospital stay.

Low-dose thrombolytic therapy versus unfractionated heparin in patients with intermediate-high risk pulmonary embolism.

Patients with intermediate-high risk pulmonary embolism (PE) who have acute right ventricular dysfunction and myocardial injury without overt hemodynamic compromise may be candidates for thrombolytic therapy (TT). In this study, we aimed to compare the clinical outcomes of low-dose prolonged TT and unfractionated heparin (UFH) in intermediate-high risk PE patients. This study enrolled 83 (female: 45 [54.2%], mean age: 70.07±10.7 years) retrospectively evaluated patients with the diagnosis of acute PE who were treated with low-dose and slow-infusion of TT or UFH. The primary outcomes of the study were de-fined as a combination of death from any cause and hemodynamic decompensation, and severe or life-threatening bleeding. Secondary endpoints were recurrent PE, pulmonary hypertension, and moderate bleeding. The initial management strategy of intermediate-high risk PE was TT in 41 (49.4%) patients and UFH in 42 (50.6%) cases. Low-dose prolonged TT was successful in all patients. While the frequency of hypotension decreased significantly after TT (22 vs. 0%, P<0.001), it did not decrease after UFH (2.4 vs. 7.1%, p=0.625). The proportion of hemodynamic decompensation was significantly lower in the TT group (0 vs. 11.9%, p=0.029). The rate of secondary endpoints was significantly higher in the UFH group (2.4 vs. 19%, P=0.016). Moreover, the prevalence of pulmonary hypertension was significantly higher in UFH group (0 vs. 19%, p=0.003). Prolonged TT regimen with low dose, slow infusion of tissue plasminogen activator was found to be associated with a lower risk of hemodynamic decompensation and pulmonary hypertension in patients with acute intermediate-high-risk PE compared to UFH.

Use of Flumazenil in Detoxification of High-Dose Benzodiazepine Users: A Mini Review of Pharmacological Basis and Clinical Studies

Introduction: The use of benzodiazepines (BDZ) is notoriously associated with significant long-term problems and it is estimated that the long-term users (LTU) in Italy are over 3 million people, including many elderly people. Unfortunately, 40 to 80% of the LTUs develop dependence and many also have tolerance, with the need for a progressive increase in the daily dosage up to the point of tolerating daily megadoses. In recent years, the off-label use of continuous infusion subcutaneous flumazenil has established itself as a viable approach for rapid hospital detoxification of these sometimes very complex clinical cases. The purpose of the article is, starting from the pharmacological and biochemical bases, to describe the mechanism of action, the areas of applicability and the possible criticalities by analyzing the Italian data. Materials and Methods: A computerized research was carried out for the articles to be inserted through use of international databases PUBMED and RESEARCHGATE by typing in keywords such as “flumazenil, high dose benzodiazepine users, use of flumazenil for benzo detoxification” and related articles. We also used the PUBCHEM database to describe some chemical and pharmacological characteristics of flumazenil. Both Italian and international research articles have been selected, starting from 1980 to today. Discussion and Conclusions: The use of flumazenil in slow infusion remains off-label but, for almost 20 years, it has been in use (in Italy and beyond) to detoxify, in about a week of hospitalization, patients with equivalent daily doses of diazepam greater than 50 mg / day for more than 6 months (with a description of cases up to 350 mg / day of diazepam-equivalent). This would allow the GABA-Argic receptor resensitization in a short time and with minimal or absent withdrawal symptoms, being able to suspend megadoses of BDZ in a very short time. In Italy this approach is still used to a limited extent and it cannot be said that it is absolutely the best method but the analysis of various endpoints in published studies, such as acute withdrawal discomfort, discharge without prescription of benzodiazepines and relapses in the first 6-12 months of discharge, certainly makes us reflect on the possibility of extending this approach to various territorial hospitals.

Liposomal Amphotericin-B Infusion-related Reactions and Rate of Infusions: A Single Center Cohort Study

Objectives: Liposomal amphotericin B is a broad-spectrum antifungal treatment used for life-threatening infections, but it commonly induces infusion-related adverse events that may prevent treatment completion. Based on anecdotal evidence, a slow infusion guideline at treatment initiation has been suggested to reduce these reactions. This study aimed to determine if slowing down the infusion rate on treatment initiation would reduce the rate of infusion-related adverse events.&#x0D; Methods: A retrospective cohort study was conducted examining the primary outcome of adverse event rates between patients who received slow and standard (2-hour or faster) infusions at a major hospital in Australia. Secondary outcomes were risk factors associated with infusion reactions. The rates of adverse events were analyzed using Fisher’s exact test.&#x0D; Results: An 8-year audit identified 47 patients who were administered liposomal amphotericin-B. The average age of the study population was 61.7 years and 28 (59.6%) were male patients. Slower than standard infusions were given to 5 (10.6%) patients on treatment initiation. Infusion-related adverse events occurred in 2 (40.0%) patients with reduced rates and 5 (11.9%) patients with standard infusion rates (p=0.154). Typical reactions were myalgia, dyspnoea, and flushing. Four patients with adverse events had been rechallenged after further rate reductions and prophylactic medications with the completion of treatment. No risk factors for adverse events were identified among demographics, comorbidities, or co-prescribed medications.&#x0D; Conclusion: Slowing the infusion rate of liposomal amphotericin-B administration does not appear to reduce the likelihood of infusion-related reactions, however, it can be trialed for adverse-event management. J Microbiol Infect Dis 2022; 12(4): 148-153.

Comparative Study Between Intravenous Clonidine and Preservative Free Intravenous Lignocaine in Attenuation of Pressor Response to Laryngoscopy and Endotracheal Intubation

Objectives To compare the attenuation of pressor responses by intravenous clonidine and preservative-free lignocaine to laryngoscopy and endotracheal intubation. Materials and Methods A randomized, prospective, comparative, double-blinded study was conducted in 80 adult patients who were randomized into two groups of 40 each, group clonidine (Group C) and group lignocaine (Group L). Group C patients were given 2 µg/kg clonidine in 20 ml of normal saline as a slow infusion over 10 min prior to intubation. Group L patients were given 1.5 mg/kg of preservative-free 2% lignocaine in 20 ml of normal saline as a single-dose infusion over 3 min prior to intubation. Baseline vital and hemodynamic parameters were monitored during the perioperative period at 1-, 5-, and 10-min post-intubation. Results The attenuation of heart rate (HR) after intubation was much better with clonidine than lignocaine as there is statistically significant difference in the mean HR between the two groups at 1, 5, and 10 min after intubation with the HR significantly lesser in the Group C than the Group L at all times after intubation. Both clonidine and lignocaine were effective in attenuating systolic blood pressure response after intubation, but clonidine was more effective than lignocaine as systolic blood pressure (SBP), diastolic blood pressure (DBP), and mean arterial pressure (MAP) in the Group C remained much lower than the Group L and the difference between the two groups was statistically significant at all times after intubation. Conclusion Premedicating with a single slow infusion of 2 µg/kg i.v. clonidine has been proven to be effective in maintaining perioperative hemodynamic stability at 1, 5, and 10 min post-intubation than lignocaine.

Self-assumed Neurologic Related Condition Deviated Metoclopramide-Induced Acute Dystonic of Oculogyric Crisis in a Woman of Childbearing Age: A Case Report

A 26-year-old Malaysian woman (childbearing age) attended a private primary care clinic with a known case of gastroesophageal reflux disease (GERD) and complained of persistent nausea and a few episodes of vomiting. She had no known drug allergy, no surgical history, no hospitalization in the last two years, was a non-smoker, and no history of drug or alcohol abuse. The patient was prescribed Tab metoclopramide 10 mg TDS and Tab ranitidine 150 mg BD for five days. About 30 min after oral administration of both medicines, her eyes rolled involuntary upward, leading to lateral deviation of the eyes, and mouth jaws clenched as if “dislocated jaws.” The patient was immediately brought into an emergency department (ED) of a public tertiary care hospital. A drug challenge test was done which resulted in the withdrawal of metoclopramide. The accompanied sister later disclosed that the patient had taken metoclopramide and ranitidine from a private clinic earlier in the day. The patient self-assumed to have a sudden seizure, due to excessive hot weather and dehydration. A slow intravenous infusion of 50 mg/mL diphenhydramine hydrochloride in 0.9% w/v NaCl 100 mL was administered stat. Consequently, the symptoms vanished after approximately 30 min of the therapy, devoid of relapse. The patient was discharged from ED post 8 hours of monitoring with complete recovery. Physicians frequently prescribe metoclopramide to treat nausea and vomiting, which may cause adverse drug reaction of acute dystonic oculogyric crisis (OGC). Due to its unwanted and unpredictable extrapyramidal symptoms, metoclopramide should be prescribed and dispensed with caution. Thorough history taking at ED is imperative for correct early diagnosis and treatment, as metoclopramide-induced dystonic OGC has a high probability of confusion with other causes of dystonia such as conversion and seizures, encephalitis, tetanus, and hypercalcemic tetany.

Rituximab Induces an Inflammatory Cytokine Response with Increased IP-10 (CXCR10) in Patients with Infusion Reactions

Most patients initiating anti-CD20 monoclonal antibody (mAb) therapy for CLL have a disruptive infusion reaction that can cause serious complications and be fatal. A better understanding of the risk factors and etiology of infusion reactions is required to improve preventative measures and management. We report a study to test the hypothesis that IV rituximab induces an inflammatory cytokines response with differences in individual cytokine concentrations correlating with infusion reactions. We designed a clinical trial (NCT03788291) for initial treatment of patients with progressive CLL that provided clinical data and blood specimens from 37 patients treated with 50 mg of IV rituximab infused at 25 mg/h. Blood specimens were collected immediately prior to initiation of rituximab (baseline), one hour later (1h), at the end of the infusion (post-infusion) and at 48 h after initiation of therapy (48h). Infusion reactions (CTCAE grade ≥2 events) were managed by interrupting the infusion and initiating symptomatic treatment. We measured circulating CLL cell counts and CD20 levels, and serum rituximab concentration, complement levels, and cytokine concentrations of IFN-γ, IL-10, IL-18, IL-2, IL-4, IL-6, IL-8, IP-10, MCP-1, MIP-1α, MIP-1β, and TNF-α using standard methods. Twenty-four (65%) patients had 25 infusion reactions (all CTCAE grade 2) at a median of 78 minutes (range 35-128) after initiation of rituximab therapy (median dose 32 mg, range 15-50). All patients completed the 50 mg rituximab infusion (median time 150 minutes, range 119-195). Patient and CLL characteristics including baseline CLL cell counts did not predict the risk of infusion reactions. Median CLL counts at 1h decreased to 14.7% of baseline with no further changes post-infusion and no significant difference between patients with or without infusion reactions (60x109/L vs. 45x109/L, p=0.61). Median CLL cell membrane CD20 levels (x103 molecules/cell) decreased from 4.77 at baseline to 3.10 at 1h (p=0.002) and 1.59 post-infusion (p<0.0001 vs. baseline and 1h) with no significant differences between patients with or without an infusion reaction. The median estimated number of circulating CLL cell membrane CD20 molecules (x1012 molecules/L) decreased from 325.8 at baseline to 34.1 at 1h (p<0.0001) and 14.5 post-infusion (p<0.0001 vs. baseline, p<0.03 vs. 1h) with no significant differences between patients with or without an infusion reaction. There was no correlation between risk of infusion reaction and serum levels of rituximab or serum complement. Thirty-five (95%) patients had a ≥4 fold increase in serum concentration of ≥1 cytokine with resolution of the cytokine response at 48h. All patients with an infusion reaction had significantly higher median post-infusion serum concentrations of IP-10, IL-6 and IL-8. All 17 patients with IP-10 serum concentrations above the limit of detection (40,000 pg/ml) post-infusion had an infusion reaction, and all 24 patients with an infusion reaction had a ≥4 fold increase in serum IP-10 concentrations. Of 13 patients without an infusion reaction, the highest measured serum IP-10 concentration was 22,013 pg/ml and only 3 (23%) had ≥4 fold increases in serum IP-10 concentrations. Slow infusion of a reduced dose of rituximab induced a cytokine response in 95% of patients and therapy disrupting infusion reactions occurred at a comparable rate (65%) to standard rituximab therapy. Infusion reactions were associated with increased levels of IP-10, IL-6 and IL-8. IP-10 levels were increased by ≥4 fold in all patients with an infusion reaction compared to 23% without an infusion reaction. These data suggest that rituximab infusion reactions are caused by inflammatory cytokines produced by cytotoxic effector cells activated by rituximab independent of the pre-treatment amount of circulating CLL cells or CD20 levels, or efficacy of rituximab in reducing the circulating CLL cell count. Infusion reactions occurred after at least 35 minutes of therapy concurrent with a rapid decrease in circulating CLL cells. This observation suggests that cytokine release could be a result of activation of effector cells responsible for CLL cell elimination. Our data provides novel insights into the potential mechanism of infusion reactions and could form the basis of further research to determine methods to control this clinically important and therapy limiting complication.

Abstract 155: Intra-arrest Epinephrine Administration is Associated with Increased Myocardial Injury and Inflammation in a Novel Murine Model of Cardiac Arrest

Introduction: Epinephrine (EPI) is routinely administered in cardiac arrest resuscitation. Using a novel murine model of cardiac arrest, this study aims to assess the effects of epinephrine on myocardial inflammation and injury. Hypothesis: Intra-arrest epinephrine use is associated with increased myocardial injury, inflammation and fibrosis. Methods: A total of 56 mice were included in the study. Both cardiac arrest (CA) and sham (SHAM) groups received intravenous potassium chloride either as a bolus (CA) or slow infusion (SHAM), inducing ECG-confirmed asystole (CA only) for 4-minutes prior to delivery of intravenous epinephrine (250ul, 30ug/ml) or saline (250ul) and manual chest compressions (300BPM) for 4-minutes (Fig A). Mice were recovered for assessments at 24- or 72-hour timepoints. Results: Rates of successful ROSC (n=21(96%) vs. n=14(82%), P=0.18) and survival to recovery (n=11(50%) vs. n=12(71%),P=0.19) were similar in CA treated with (CA+EPI) and without (CA-Epi) EPI, respectively. Greater myocardial injury occurred in CA+EPI, compared to CA-Epi, with increased Hs-Troponin levels measured at 24- (26.0±0.9ng/mL vs. 9.4±5.3,P=0.015) and 72-hours (20.9±8.3ng/mL vs. 5.0±2.4,P=0.012) (Fig B). To examine mRNA expression in cardiac tissue, rt-PCR was performed. At 72-hours, CA+EPI, compared to CA-EPI, was associated with significantly increased expression of inflammatory (TNF-α, IL1β, IL10, F4-80 and CD68) and fibrotic (TGFβ, Col1 and Col3) genes. There was no difference between SHAM-EPI and SHAM+EPI at 72-hours (Fig C). Conclusion: In a mouse model of cardiac arrest, the use of epinephrine did not improve rates of ROSC and survival. However, epinephrine exposure was associated with increased biomarkers of myocardial injury, end-organ inflammation, and fibrosis. These findings underscore the need for further pre-clinical studies to assess alternate agents that confer protection to vital organs and improve rates of survival.

S1396 Response-Guided Ascites Mobilization in Patients of Acute on Chronic Liver Failure (ACLF) With Acute Kidney Injury Treated With Slow Albumin, Furosemide and Vasoconstrictor Therapy (SAFI+T) versus Standard Treatment

Introduction: Acute-on-chronic liver failure (ACLF) with increasing organ failure is associated with poor outcome. Severely deranged systemic hemodynamic and decreased effective arterial blood volume contributes to tissue damage and organ failure. Response guided therapy with albumin, vasoconstrictors and furosemide may help overcome effective hypovolemia improve diuresis and impact survival. Methods: In observation cohort, 56 patients with ACLF (CANONIC criteria) complicated with AKI ( S.Cr ³ 1.5, >50% increased S.cr from baseline), ascites (≥ Grade II) were enrolled. 30 patients (GROUP I) received response guided(Urine sodium >80mmol/day) slow albumin-furosemide infusion ± terlipressin (SAFI±T), while 26 patients (GROUP II) received standard medical therapy. 28-day survival, ascites mobilization (nil or grade 1), reversal of AKI and adverse events were noted. Laboratory evidences for improvement in various pathophysiological alterations; endotoxemia, cytokine storm, neutrophil dysfunction and secondary infections, following SAFI±T were evaluated. Results: Alcohol and sepsis were the commonest etiologies for chronic and acute insult respectively. Ascites was completely mobilized in 18/30 (60%) patients in Group I (SAFI±T) and 7/26 (26.9%) in Group II (p< 0.05). At 28 days the survival analysis showed, Group I 23/30 (76.4%) and Group II 14/26 (53.8%) (P=< 0.05). There was a lower incidence of hospital acquired infection in Group I of 6.7% vs 38.4% in Group II (p=0.05) and the same was reflected in serum endotoxin and pro-inflammatory cytokine levels; IL-6 and IL-1b showed significant reduction in Group I. Serum endotoxin and TNF-a level increased in Group II despite SMT while it showed significant fall in SAFI+T arm post treatment. Renal artery resistive index was significantly lower after SAFI(T) therapy (0.84 to 0.72) (p< 0.05) as similar trend emulated in UNa level. Conclusion: Patients with ACLF treated with SAFI+T protocol had higher natriuresis, enhanced urine output, complete ascites removal, and improved renal function with a faster mean duration of treatment and better 28-day survival. An in-hospital infection rate was lower. Ascites mobilization was associated with improvement in gut permeability, endotoxemia, pro-inflammatory cytokines, and NETosis in the SAFI+T cohort, showing an association between ascites mobilization and improved pathophysiologic dysfunctions.

Study of Compliance, Pattern of Treatment Interruption and Adverse Events Reported by Anaemic Pregnant Women Receiving the Parenteral Iron Sucrose Therapy

Background: In spite of many efforts by the government since independence anaemia in pregnant women has shown resistance to improvement. Aim: The main aim was to study the compliance of parenteral iron sucrose therapy in pregnant woman along with an additional objective which was to study the pattern of treatment interruption and adverse events observed by them. Methods: This study was conducted by the Department of Community Medicine in the rural and urban field practice area of district Nuh. A list of three hundred and eighty four anaemic pregnant females put on IVIS therapy, fetched from the health centre and relevant details were documented. Result: Out of total of 384 study participants, 291 (75.8%) were compliant with IVIS therapy i.e., they received all four doses. Out of total 93 either non-compliant or partially compliant subjects, most of them (51.6%, n=48) missed 3 doses whereas 22 participants (23.7%) missed 2 doses of the IVIS therapy. Ten study participants (10.7%) showed non-compliance to the therapy. Multigravida subjects were either non or partial compliant compared to primigravida. The three most common adverse events recorded at the time of infusion of 1st dose of IVIS therapy were swelling at injection site, pruritus, and muscle pain or joint pain experienced by 32 (8.3%), 17 (4.4%) and 16 (4.2%) study participants respectively. Conclusion: IVIS therapy is relatively safe therapy and well tolerated by anaemic pregnant females when given as slow infusion. Multigravida subjects were either non or partial compliant compared to primigravida females for IVIS therapy.

High-Dose Intravenous Iron with Either Ferric Carboxymaltose or Ferric Derisomaltose: A Benefit-Risk Assessment.

The intravenous iron formulations ferric carboxymaltose (FCM) and ferric derisomaltose (FDI) offer the possibility of administering a large amount of iron in one infusion. This results in faster correction of anemia and the formulations being better tolerated than oral iron formulations. This triad of logistic advantages, improved patient convenience, and fast correction of anemia explains the fact that intravenous iron formulations nowadays are frequently prescribed worldwide in the treatment of iron deficiency anemia. However, these formulations may result in hypophosphatemia by inducing a strong increase in active fibroblast growth factor-23 (FGF-23), a hormone that stimulates renal phosphate excretion. This effect is much more pronounced with FCM than with FDI, and therefore the risk of developing hypophosphatemia is remarkably higher with FCM than with FDI. Repeated use of FCM may result in severe osteomalacia, which is characterized by bone pain, Looser zones (pseudofractures), and low-trauma fractures. Intravenous iron preparations are also associated with other adverse effects, of which hypersensitivity reactions are the most important and are usually the result of a non-allergic complement activation on nanoparticles of free labile iron—Complement Activation-Related Pseudo-Allergy (CARPA). The risk on these hypersensitivity reactions can be reduced by choosing a slow infusion rate. Severe hypersensitivity reactions were reported in < 1% of prospective trials and the incidence seems comparable between the two formulations. A practical guideline has been developed based on baseline serum phosphate concentrations and predisposing risk factors, derived from published cases and risk factor analyses from trials, in order to establish the safe use of these formulations.

Response Guided Slow Infusion of Albumin, Vasoconstrictors and Furosemide Improves Ascites Mobilization and Survival in Acute on Chronic Liver Failure: A Proof-of-Concept Study.

Background and AimsAcute-on-chronic liver failure (ACLF) with increasing organ failure is associated with poor outcomes. Severely deranged systemic hemodynamics and decreased effective arterial blood volume contribute to tissue damage and organ failure. Response-guided therapy with albumin, vasoconstrictors, and furosemide may help overcome effective hypovolemia, improve diuresis and impact survival.MethodsIn the observation cohort, 230 patients with ACLF (CANONIC criteria) with ascites (≥Grade II) and ACLF ≥Grade I were enrolled. A total of 136 patients (GROUP I) received response-guided (urine sodium >80mmol/day) slow albumin-furosemide infusion ± terlipressin (SAFI ± T), while 94 patients (GROUP II) received standard medical therapy. Twenty-eight-day survival, ascites mobilization (nil or grade 1), and adverse events were noted. In another mechanistic cohort (n = 40), laboratory evidences for improvement in various pathophysiological alterations; gut permeability, endotoxemia, cytokine storm, neutrophil dysfunction, and hemodynamic alterations following SAFI ± T/Noradrenaline (NAdr) were evaluated.ResultsAge, gender, CLIF-C-ACLF, SOFA and MELD scores, ACLF grades and urine sodium were not different between the two groups in the observation cohort. Ascites was mobilized in 102/136 in GROUP I (SAFI ± T) and 23/94 in GROUP II (p < 0.05). Twenty-eight-day survival was significantly higher in GROUP I = 103/136 (75.7%) vs GROUP II = 50/94 (53.2%), (P = <0.001). All those who were unable to reach urine sodium >80 mmol/day died. Four patients in GROUP I developed scrotal gangrene. In the mechanistic cohort, 72% of patients survived with significant improvement in gut permeability, endotoxemia, serum cytokines, neutrophil dysfunction, and hemodynamic alterations.ConclusionAscitic fluid mobilization by response-guided SAFI ± T/NAdr therapy improves survival by improving splanchnic and systemic hemodynamics, decreasing gut congestion, gut permeability, and endotoxemia, improving neutrophil functions, and reducing pro-inflammatory cytokines in circulation.

337.3: Effects of Tacrolimus on Mechanical and Humoral Determinants of Brain Death-Induced Lung Injury

Background: Donor brain death-induced lung injury may compromise graft function after transplantation. The mechanisms of this particular form of neurogenic lung edema and its possible prevention by immunomodulator Tacrolimus remain incompletely understood. Methods and Results: Brain death was induced, by slow intracranial infusion of blood, in anesthetized pigs after randomisation to placebo (n=9) or to Tacrolimus (n=8). One, three, five and seven hours after brain death, pulmonary artery pressure (Pap), wedged Pap (Papo), right atrial pressure (Pra), effective pulmonary capillary pressure (Pcap), systemic artery pressure (Psa) and thermodilution cardiac output (Q) were measured. Blood and lung tissue were sampled and lung injury scored on pathological examination. Brain death was associated with marked increases in Pap, PVR and Pcap, decreases in Psa and Q with growing need for Noradrenaline while Ppao and Pra remained in a physiological range. Arterial O2 pressure to fraction of inspired O2(PaO2/FiO2) decreased. Brain death was associated with increased lung injury score together with increased gene expressions of interleukin (IL)-6 and IL-1b, heme-oxygenase-1, signal transducer and activator of transcription-3. Lung tissue pro-inflammatory IL-6/IL-10 ratio was decreased and pro-apoptotic Bax/Bcl2 ratio was increased. Tacrolimus partially corrected pulmonary hypertension and lung tissue biological perturbations. PaO2/FiO2 was inversely correlated to PCP and lung injury score. Serum IL-6 and IL-1b were correlated to PCP. Conclusion: Brain death induced lung injury is related to effective pulmonary capillary hypertension with normal PAWP and pro-inflammatory and pro-apoptotic biological changes all partially reversed by preventive Tacrolimus treatment.

A randomised preclinical trial of adrenaline use during cardiac arrest in mice

BackgroundAdrenaline is routinely administered during cardiac arrest resuscitation. Using a novel murine model of cardiac arrest, this study evaluates the effects of adrenaline use on survival and end-organ injury. MethodsA total of 58 mice, including cardiac arrest (CA) and sham (SHAM) groups received intravenous potassium chloride either as a bolus (CA) or slow infusion (SHAM), inducing ECG-confirmed asystole (in CA only) for 4-minutes prior to intravenous adrenaline (+ADR;250 ul,32 ug/ml) or saline (-ADR;250 ul) and manual chest compressions (300 BPM) for 4-minutes. Mice with return of spontaneous circulation (ROSC) were assessed at 24- or 72-h timepoints. ResultsAmong animals that underwent CA, rates of ROSC (n = 21 (95 %) vs n = 14 (82 %), P = 0.18) and survival to the planned endpoint (n = 11 (50 %) vs n = 12 (71 %), P = 0.19) were similar when comparing those treated with (CA+ADR) and without (CA-ADR) adrenaline. However, in CA animals that initially achieved ROSC, subsequent mortality was approximately 3-fold greater with adrenaline treatment (48 % vs 14 %, P = 0.042). Among SHAM animals, adrenaline use had no impact on survival rates or other endpoints. Greater myocardial injury occurred in CA+ADR vs CA-ADR, with increased Hs-Troponin levels measured at 24- (26.0 ± 0.9 vs 9.4 ± 5.3 ng/mL, P = 0.015) and 72-h (20.9 ± 8.3 vs 5.0 ± 2.4 ng/mL, P = 0.012), associated with increased expression of pro-inflammatory and fibrotic genes within cardiac and renal tissue. ConclusionAdrenaline did not improve ROSC or overall survival but following successful ROSC, its use resulted in 3-fold greater mortality rates. Adrenaline was also associated with increased myocardial injury, end-organ inflammation, and fibrosis. These findings underscore the need for further preclinical evaluation of alternate pharmacologic adjuncts for cardiopulmonary resuscitation that improve survival and limit end-organ injury.

The effect of age on electroencephalogram measures of anesthesia hypnosis: A comparison of BIS, Alpha Power, Lempel-Ziv complexity and permutation entropy during propofol induction.

BackgroundImproving anesthesia administration for elderly population is of particular importance because they undergo considerably more surgical procedures and are at the most risk of suffering from anesthesia-related complications. Intraoperative brain monitors electroencephalogram (EEG) have proved useful in the general population, however, in elderly subjects this is contentious. Probably because these monitors do not account for the natural differences in EEG signals between young and older patients. In this study we attempted to systematically characterize the age-dependence of different EEG measures of anesthesia hypnosis.MethodsWe recorded EEG from 30 patients with a wide age range (19–99 years old) and analyzed four different proposed indexes of depth of hypnosis before, during and after loss of behavioral response due to slow propofol infusion during anesthetic induction. We analyzed Bispectral Index (BIS), Alpha Power and two entropy-related EEG measures, Lempel-Ziv complexity (LZc), and permutation entropy (PE) using mixed-effect analysis of variances (ANOVAs). We evaluated their possible age biases and their trajectories during propofol induction.ResultsAll measures were dependent on anesthesia stages. BIS, LZc, and PE presented lower values at increasing anesthetic dosage. Inversely, Alpha Power increased with increasing propofol at low doses, however this relation was reversed at greater effect-site propofol concentrations. Significant group differences between elderly patients (>65 years) and young patients were observed for BIS, Alpha Power, and LZc, but not for PE.ConclusionBIS, Alpha Power, and LZc show important age-related biases during slow propofol induction. These should be considered when interpreting and designing EEG monitors for clinical settings. Interestingly, PE did not present significant age differences, which makes it a promising candidate as an age-independent measure of hypnotic depth to be used in future monitor development.

Safety and Efficacy of Bleomycin Slow Infusion Sclerotherapy Using a Syringe Pump for Microcystic and Mixed Lymphatic Malformations.

To evaluate the safety and efficacy of bleomycin infusion sclerotherapy using a syringe pump in microcystic and mixed (microcystic components with the presence of a cyst over 1cm) lymphatic malformations (LMs). Patients who received bleomycin sclerotherapy with a syringe pump for microcystic or mixed LMs were reviewed. Cystic components of LMs were accessed under sonographic guidance, followed by injection of an opacified bleomycin solution using a syringe pump (infusion rate, 10-20mL/h) under fluoroscopic guidance. Imaging outcomes were graded as complete (> 90% size reduction), partial (25-90%), or no response (< 25%). Clinical outcomes and procedure-related complications were also reviewed. Forty-nine patients with 81 sclerotherapies were analyzed. The mean age was 17years (range 0.1-65 y). Thirty-one (63%) patients had microcystic LMs, and 18 (37%) had mixed. A mean of 1.7 sessions (range 1-4) of sclerotherapy was performed using a mean cumulative dose of bleomycin of 10.8 U (range 1.5-39 U). The mean infusion time was 39min (range 14-130min). Regarding imaging outcomes, there was a complete response in 29% (n = 14), a partial response in 57% (n = 28), and no response in 14% (n = 7). Regarding clinical outcomes, there was a complete response in 39% (n = 19), a partial response in 51% (n = 25), and no response in 10% (n = 5). According to the CIRSE classification, no major complications were identified. Bleomycin slow infusion sclerotherapy provides gradual filling of sclerosant to target microcystic components. This technique is safe and feasible for the management of microcystic or mixed LMs. Level 4, Case series.

Fast versus slow infusion of 20% albumin: a randomized controlled cross-over trial in volunteers

BackgroundWe investigated whether plasma volume (PV) expansion of 20% albumin is larger when the fluid is administered rapidly compared with a slow infusion.MethodsIn this open-labeled randomized interventional controlled trial, 12 volunteers (mean age, 28 years) received 3 mL/kg of 20% albumin (approximately 225 mL) over 30 min (fast) and 120 min (slow) in a cross-over fashion. Blood hemoglobin and plasma albumin were measured on 15 occasions during 6 h to estimate the PV expansion and the capillary leakage of albumin and fluid.ResultsThe largest PV expansion was 16.1% ± 6.5% (mean ± SD) for fast infusion and 12.8% ± 4.0% for slow infusion (p = 0.52). The median area under the curve for the PV expansion was 69% larger for the fast infusion during the first 2 h (p = 0.034), but was then similar for both infusions. The half-life of the PV expansion did not differ significantly (median, 5.6 h versus 5.4 h, p = 0.345), whereas the intravascular half-life of the excess albumin was 8.0 h for fast infusion and 6.3 h for slow infusion (p = 0.028). The measured urine output was almost three times larger than the infused volume. The plasma concentration of atrial natriuretic peptide (MR-proANP) accelerated the capillary leakage of albumin and the urine flow.ConclusionsThe intravascular persistence of albumin was longer, but the fluid kinetics was the same, when 20% albumin was infused over 30 min compared with 120 min. We found no disadvantages of administering the albumin at the higher rate.Trial registration EU Clinical Trials Register, EudraCT2017-003687-12, registered September 22, 2017, https://www.clinicaltrialsregister.eu/ctr-search/trial/2017-003687-12/SE

Ceftriaxone Induced Anaphylaxis Reaction Following Negative Intradermal Skin Tested Patient: A Rare Case Report

Anaphylaxis is a severe life-threatening reaction that may be associated with exposure to a variety of drug classes. β-lactam antibiotics and nonsteroidal anti-inflammatory drugs (NSAIDs) are most common classes of drugs causing anaphylaxis. Intradermal skin test (IST) is required in absence of previous history of allergy to antibiotics. In spite of negative intradermal skin testing, our patient had severe anaphylactic reaction after ceftriaxone administration but was managed successfully. This case report reflects the limitations of screening test done preoperatively for the diagnosis of sensitization to ceftriaxone antibiotic drug. Key Messages: Intradermal skin test is mandatory in all patients receiving first exposure of any new antibiotic drug. When a patient is negative after intradermal skin test, the drug should be given as slow intravenous infusion to prevent sudden and dreadful cardiovascular collapse.

Evaluating the effect of Edaravone on clinical outcome of patients with severe COVID-19 admitted to ICU: a randomized clinical trial.

Cytokine storm is the most prominent hallmark in patients with coronavirus disease 2019 (COVID-19) that stimulates the free radical storm, both of which induce an overactive immune response during viral infection. We hypothesized that owning to its radical-scavenging and anti-inflammatory properties, Edaravone could reduce multi-organ injury, clinical complications, and mortality in severe COVID-19 cases. This single-center randomized clinical trial was accompanied in the intensive care units (ICUs) of the teaching hospital of Tabriz University of Medical Sciences to evaluate the effect of Edaravone on the outcome of patients with severe COVID-19. Thirty-eight patients admitted to ICU were included and randomized into two control and intervention arms. Patients in the intervention group received 30 mg Edaravone by slow intravenous infusion for three days in addition to receiving national therapy. The primary outcome was the need for intubation, the intubation length, and mortality rate. Secondary endpoints were clinical improvement. Edaravone administration improved the primary outcomes; it decreased the need for endotracheal intubation and mechanical ventilation [10.52% (n = 2) versus 42.1% (n = 8); p = 0.03] and intubation length [3 (1–7) versus 28 (4–28), p = 0.04] compared to control group. Baseline characteristics and laboratory tests were similar between the studied groups. No marked differences were observed in secondary endpoints (p > 0.05). Administration of Edaravone could decrease the need for mechanical ventilation and length of intubation in severe COVID-19 patients admitted to ICU.