Duration Of Infusion Research Articles

Otoprotective Effects of Sodium Thiosulfate by Demographic and Clinical Characteristics: A Report From Children's Oncology Group Study ACCL0431.

ACCL0431 was a randomized clinical trial that demonstrated efficacy of sodium thiosulfate (STS) for preventing cisplatin-induced hearing loss (CIHL) among patients 1-18years old. The purpose of this study was to evaluate possible differential STS otoprotection among patient subgroups. This secondary analysis included ACCL0431 participants treated with cisplatin and randomized to receive STS or not (observation). Hearing status was obtained at 4weeks and 12months post cisplatin therapy (SIOP Ototoxicity Scale). Cumulative incidence of CIHL (Grade 1+) was assessed across age, sex, race/ethnicity, cancer diagnosis, and cisplatin infusion duration. Associations between these variables and CIHL were assessed using multivariable logistic regression. Interaction terms were used to evaluate potential heterogeneity in STS effect sizes across subgroups. Among evaluable participants (n = 121), CIHL incidence was 22.4% with STS and 54.0% with observation. Odds of developing CIHL were greatest among children less than 5years versus older (randomization-adjusted odds ratio [OR] 2.94, 95% CI: 1.30-7.14) and those with neuroblastoma, hepatoblastoma, or medulloblastoma versus germ cell tumor or osteosarcoma (age- and randomization-adjusted OR 11.26, 95% CI: 3.08-47.35). STS otoprotective effect sizes were also greatest in the same highest risk groups by age (<5years: OR 0.08, 95% CI: 0.02-0.32; ≥5years: OR 0.39, 95% CI: 0.15-1.06) and cancer diagnosis (neuroblastoma/hepatoblastoma/medulloblastoma: OR 0.1, 95% CI: 0.02-0.45; germ cell tumor/osteosarcoma: OR 0.32, 95% CI: 0.06-1.25). Significant otoprotection from STS was noted across other subgroups with varied magnitudes of effect. STS otoprotection appears to differ across clinically meaningful subgroups, particularly age at diagnosis. These results inform clinical decision-making and future research.

PKPD modelling and simulation of longitudinal meropenem in vivo effects against Escherichia coli and Klebsiella pneumoniae strains with high MIC

BackgroundCarbapenem-resistant bacteria pose a threat to public health. Characterizing the pharmacokinetics-pharmacodynamics (PKPD) of meropenem longitudinally in vivo against resistant bacteria could provide valuable information for development and translation of carbapenem-based therapies. ObjectivesTo assess the time course of meropenem effects in vivo against strains with high MIC to predict PK/PD indices and expected efficacy in patients using a modelling approach. MethodsA PKPD model was built on longitudinal bacterial count data to describe meropenem effects against six Escherichia coli and Klebsiella pneumoniae strains (MIC values 32-128 mg/L) in a 24h mouse thigh infection model. The model was used to derive PK/PD indices from simulated studies in mice and to predict the efficacy of different infusion durations with high-dose meropenem (2 g q8h/q12h for normal/reduced kidney function) in patients. ResultsData from 592 mice were available for model development. The estimated meropenem concentration-dependent killing rate was not associated with differences in MIC. The fraction of time that unbound concentrations exceeded EC50 (fT>EC50, EC50=1.01 mg/L) showed higher correlations than fT>MIC. For all investigated strains, bacteriostasis at 24h was predicted for prolonged infusions of high-dose meropenem monotherapy in >90% of patients. ConclusionsThe developed PKPD model successfully described bacterial growth and meropenem killing over time in the thigh infection model. For the investigated strains the MIC, determined in vitro, or MIC-based PK/PD indices, did not predict in vivo response. Simulations suggested prolonged infusions of high-dose meropenem to be efficacious in patients infected by the studied strains.

Reprint of: Does Two-Step Infusion Improve the Pharmacokinetics/Pharmacodynamics Target Attainment of Meropenem in Critically Ill Patients?

The optimal method for administering meropenem remains controversial. This study was conducted to explore the optimal two-step infusion strategy (TIT), and to investigate whether TIT is superior to intermittent infusion therapy (IIT) and prolonged infusion therapy (PIT). A physiologically based pharmacokinetics model for critically ill patients was established and evaluated. The validated model was utilized to evaluate the pharmacokinetics/pharmacodynamics (PK/PD) target attainment of meropenem. The PK/PD target attainment of different TITs varied greatly, and the total infusion duration and the first-step dose greatly affected these values. The optimal TIT was 0.25 g (30 min) + 0.75 g (150 min) at MICs of ≤2 mg/L, and 0.25 g (45 min) + 0.75 g (255 min) at MICs of 4-8 mg/L. The PK/PD target attainment of optimal TIT, PIT, and IIT were 100 % at MICs of ≤1 mg/L. When MIC increased to 2-8 mg/L, the PK/PD target attainment of optimal TIT was similar to that of PIT and higher than IIT. In conclusion, TIT did not significantly improve the PK/PD target attainment of meropenem compared with PIT. IIT is adequate at MICs of ≤1 mg/L, and PIT may be the optimal meropenem infusion method in critically ill patients with MICs of 2-8 mg/L.

Long-term safety and tolerability of hyaluronidase-facilitated subcutaneous immunoglobulin 10% as maintenance therapy for chronic inflammatory demyelinating polyradiculoneuropathy: Results from the ADVANCE-CIDP 3 trial.

Hyaluronidase-facilitated subcutaneous immunoglobulin (fSCIG) consists of subcutaneous human immunoglobulin G (IgG) 10% with recombinant human hyaluronidase (rHuPH20) and can be administered at the same dose and interval as intravenous IgG (IVIG). fSCIG recently received US approval as maintenance therapy for adults with chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) and European approval for adults and children with CIDP after stabilization with IVIG. ADVANCE-CIDP 3 (NCT02955355) was an open-label long-term extension of the Phase 3 double-blind randomized placebo-controlled ADVANCE-CIDP 1 study (NCT02549170) that examined fSCIG safety and efficacy as maintenance CIDP therapy. Primary outcomes were safety, tolerability, and immunogenicity. Efficacy was an exploratory outcome. The study provided 220 patient-years of follow-up data from 85 patients. Median (range) exposure was 33 (0-77) months. Patients received fSCIG every 4 weeks (88.2%) or every 3 weeks (11.8%). Median (range) 4-weekly IgG dose equivalent was 64.0 (28.0-200.0) g. Mean (standard deviation) infusion duration was 135.5 (62.8) minutes. Most adverse events (AEs) were mild or moderate and self-limiting. Of the 1406 AEs, only 48 were severe and 30 were serious. fSCIG-related AEs (n = 798) included infusion site reactions such as pain, redness, and pruritus. Three infusions (0.1%) were reduced in rate, interrupted, or stopped due to intolerability. Relapse occurred in 10 of 77 patients (13.0%); annual relapse rate was 4.5%. An anti-rHuPH20 antibody titer ≥1:160 was detected in 14 of 84 patients (16.7%); patients who tested positive (≥1:160) had similar relapse rates versus those who tested negative (16.7% vs. 12.3%, respectively). ADVANCE-CIDP 3 demonstrated favorable fSCIG long-term safety and tolerability consistent with its established safety profile, and a low relapse rate, supporting use as maintenance CIDP treatment.

‘Tabs versus Jabs’ time and motion study involving experiential learning student pharmacists: how long to prepare intravenous versus oral antibiotics?

Abstract Introduction Approximately one-third of inpatients in Scotland are prescribed antibiotics1. Patients prescribed IV antibiotics should be reviewed regularly and switched to oral therapy when clinically appropriate. Optimising IV to oral switch (IVOST) is often perceived as challenging2 and risks associated with IV access and patient comfort benefits to IVOST are well known. Workforce time required to administer IV medicines compared to oral equivalents is rarely considered in the risk-benefit assessment to IVOST2. To quantify this difference, a medicines administration time and motion study was undertaken. Aim To conduct a time and motion study to explore antibiotic administration in NHS Lanarkshire (NHSL) district general hospitals: University Hospitals Hairmyres, Wishaw, and Monklands. Objectives To measure time taken by nursing staff to prepare and administer IV/oral antibiotics. To explore potential nursing time saved if IVOST. To make recommendations to NHSL’s Antimicrobial Management Committee on inpatient antibiotic use. To involve final year Student Pharmacists in a multidisciplinary (MDT) project during placement. Methods Data were collected by Student Pharmacists on Antimicrobial/Surgical Experiential Learning (EL) placements as a novel approach to specialist EL. Data were collected during midday medication rounds in a surgical ward at each hospital. Nurses were observed administering antibiotics and the time taken recorded included medicine preparation; patient identification; assessment of peripheral venous catheter; and gathering IV equipment. The timer stopped when medication was administered to the patient. IV infusion duration was not included. Data were recorded in an Excel spreadsheet in HH:MM:SS. This study did not require review by an NHS Research Ethics Committee under the updated Governance Arrangements for Research Ethics Committees (GAfREC) 2020 Edition; although local permission was sought from service leads. Results Mean nursing time to prepare IV antibiotic administration was 11 minutes 55 seconds (n=20). Mean nursing time for oral administration was 1 minute 59 seconds (n=10). Nursing staff take 6 times longer to prepare IV compared to oral antibiotics for patient administration. Potential nursing time saved per individual IVOST is approximately 10 minutes. Discussion/Conclusion Results suggest IVOST would reduce nursing time involved in medicines administration, with IVOST for one patient taking antibiotics three times daily potentially saving 30 minutes of nursing time alone. Some antibiotics have excellent oral bioavailability and this project highlights the need to educate clinical teams on selecting oral route for high bioavailability antibiotics when safe and clinically appropriate. Student pharmacists observed that nurses managed multiple interruptions and spent time looking for IV equipment, commenting that IV antibiotics produced more waste (single use plastics, syringes, packaging). Student pharmacists had a better understanding of medicines administration and nursing roles following involvement in the study. Limitations Small sample size, time constraints, data did not include infusion durations or administrations outside drug rounds. Benefits of IVOST are well known and the results of this study are comparable to similar studies in the UK. NHSL’s Antimicrobial Team are disseminating key information from this study in line with local and national guidelines. Student Pharmacists effectively contributed to a novel EL placement project and this improved their understanding of nursing roles within the MDT.

Efficacy and safety of reduced-dose and slow-infusion intravenous alteplase regimen in patients with acute pulmonary embolism at intermediate-high-risk

Abstract Background In patients with intermediate-high-risk (IHR) pulmonary embolism (PE), full-dose systemic thrombolytic treatment (STT) has been documented to lower the risk of hemodynamic decompensation and mortality, at the expense of an elevated risk of life-threatening bleeding. In this study, we aimed to evaluate the safety of reduced-dose STT regimen while maintaining effective reperfusion. Methods This single-center study comprised 124 retrospectively evaluated patients (female 58.9 % and mean age 55.4+15.8 years) diagnosed with acute PE at IHR status in accordance with European Society of Cardiology (ESC) 2019 acute PE guidelines in whom intravenous (i.v.) alteplase treatments were utilized. Patients fulfilling at least one of the following criteria have been included in the study: systolic blood pressure ≤ 110 mm Hg, heart rate &amp;gt; 100 bpm, SaO2 &amp;lt; 90 % on room air, respiratory rate &amp;gt; 20 breaths per minute, or serum lactate &amp;gt; 2 mmol/L. Exclusion criteria were any contraindication for STT and symptom onset &amp;gt; 14 days. Standard protocol for initial STT was i.v. infusion of alteplase of 25 mg over 4-6 hours. After completion of the infusion, a second STT in the same manner if one of the following criteria were present; heart rate &amp;gt; 100 bpm, SaO2 &amp;lt; 90 % or signs of organ hypoperfusion. Results Syncope and concomitant deep vein thrombosis were documented in 27.4 % and 49.2 % of patients, respectively. Baseline vital measures were as follows; heart rate: 112 +16.6 bpm, systolic blood pressure: 123+14.9 mm Hg, SaO2: 89 % (85-93), serum lactate 2.35 (1.6-2.9) mmol/L. Median alteplase dose and infusion duration were 50 (25-50) mg and 6 (4-10) hours, respectively. There were significant improvements in clinical parameters, pulmonary thrombus burden, pressure strain and right ventricular size and function as assessed by computed tomography and echocardiography (p&amp;lt; 0.001 for all). Minor and major bleeding events occurred in 3.2 % and 4.8 % of patients, respectively. One major bleed was due to cerebellar hemorrhage, but did not require surgery and patient was discharged without sequela. There were 6 (4.8 %) in-hospital deaths in which 2 were attributed to major hemorrhages and 4 due to hemodynamic decompensation. Conclusion In patients with acute IHR PE, reduced-dose and slow-infusion i.v. alteplase regimen seems to be a clinically relevant and safe reperfusion alternative to full-dose STT protocols associated with well-known major bleeding risks.

Efficacy and safety of the ultraslow low-dose thrombolytic regimen for mechanical prosthetic valve thrombosis: a prospective cohort study

Abstract Background Mechanical prosthetic valve thrombosis (MPVT) remains a significant and life-threatening complication. While surgery is here considered the gold standard therapy, it has a high perioperative risk in the acute setting. Preliminary evidence suggests that an ultraslow low-dose thrombolytic regimen may offer a safer and equally effective alternative compared to both conventional fast-infusion thrombolytic approaches or surgical options. Purpose We aimed at evaluating efficacy and safety of a previously described ultraslow low-dose thrombolytic regimen for treating acute MPVT in hospitalized adult patients. Methods This prospective single-center cohort study included all consecutive adult patients with acute MPVT treated with our ultraslow low-dose thrombolytic regimen. Patients with contraindication to thrombolytic therapy or left-sided MPVT with a minimum thrombus size of 0.8 cm2 or severe dyspnea with NYHA FC IV were excluded, and considered candidate to surgery. The regimen here used consisted of 25 mg rtPA infused over 25 hours. If initially failed, a repeat 6-hour infusion of 25 mg rtPA was administered up to a maximum total cumulative dose of 150 mg or until an adverse event occurred. The primary objective was the rate of complete MPVT resolution, defined as &amp;gt;75% reduction in the obstructive gradient by transthoracic echocardiography, less than 10 degrees residual constraint in opening and closing valve motion angles as quantified by fluoroscopy, and alleviation of patients’ thrombosis-associated symptoms or signs. Results From April 2018 to November 2023, 135 infusions of thrombolytic therapy were administered in 118 patients (median age: 35 years (IQR, 25-49); 59 [50%] women) (Table 1). 12 patients had more than one episode of MPVT during the study period. Obstructive prosthetic valve thrombosis occurred in 89.6% (121/135) of cases. Pulmonary valves were most frequently affected (n = 84, 62.2%), followed by tricuspid (n = 34, 25.2%), mitral (n = 10, 7.4%), and aortic (n = 7, 5.2%) valves. A complete thrombolysis success was achieved in 119/135 episodes of thrombolytic therapy (88.1%); of these, 47/119 patients (39.5%) responded after the first thrombolytic dose. The median total dose administered was 50 mg (IQR, 25-75) over a median infusion duration of 30 hours (IQR, 25-36). Four patients responded partially to the regimen, six patients were candidates for bailout surgery, and only one fatal intracranial bleeding occurred. No other thromboembolic or bleeding adverse events were observed. Conclusion This is the largest prospective evaluation on the safety and efficacy of the ultraslow low-dose thrombolytic regimen, which proved highly effective - in this prospective cohort - in achieving prosthetic valve thrombosis resolution with minimal complications. Further larger clinical trials are warranted.Table 1- baseline CharacteristicsStudy Outcomes

Risk factors for Relative and Absolute Hypoglycemia in Patients Treated for Diabetic Ketoacidosis and Hyperosmolar Hyperglycemic Syndrome.

Introduction: Glycemic management in the intensive care unit is an evolving practice area. This evolution has included the refinement of blood glucose targets, matching glycemic management to premorbid status, and investigations into the impact of glycemic variability and relative hypoglycemia on ICU outcomes. The interplay between these phenomena and absolute hypoglycemia has yet to be investigated in hyperglycemic emergencies. Objectives: To examine the incidence of and risk factors for relative hypoglycemia and absolute hypoglycemia in patients admitted to an intensive care unit for the management of hyperglycemic emergencies. Methods: This was a retrospective, single-center, exploratory analysis of adults admitted to the medical intensive care unit for diabetic ketoacidosis or hyperosmolar hyperglycemic syndrome. The primary outcome was the incidence of relative hypoglycemia, defined as a blood glucose level 30% lower than baseline. The baseline was determined by the estimated average blood glucose calculated from hemoglobin A1c within 3 months of index admission. Secondary outcomes were ICU length of stay, glycemic variability, and incidence of absolute hypoglycemia.Results: Relative hypoglycemia was observed in 60% of patients in the cohort. Longer insulin infusion duration and higher hemoglobin A1c levels were found to statistically increase the risk of developing relative hypoglycemia. Higher glycemic variability and longer ICU length of stay were associated with the risk of developing absolute hypoglycemia. Conclusions: Relative hypoglycemia is a frequent occurrence in this patient population. Hemoglobin A1c and duration of the insulin infusion statistically influenced the risk of developing relative hypoglycemia. Higher glycemic variability and longer ICU stay were significantly associated with developing absolute hypoglycemia. While relative hypoglycemia is common in hyperglycemic emergencies, the clinical impact remains uncertain and warrants additional investigation.

Lefamulin dosing optimization using population pharmacokinetic and pharmacokinetic/pharmacodynamic assessment in Chinese patients with community-acquired bacterial pneumonia.

Lefamulin is the first pleuromutilin antibiotic approved for the treatment of community-acquired bacterial pneumonia (CABP). However, the pharmacokinetic/pharmacodynamic (PK/PD) characteristics in Chinese CABP patients are not fully understood. This study aimed to evaluate its microbiological efficacy against Streptococcus pneumoniae and Staphylococcus aureus via PK/PD analysis. The population PK (PopPK) model, established with foreign data was validated using data from Chinese CABP patients. PK/PD analysis was conducted for the intravenous administration of 150mg q12h for 1-h, 1.5-h and extended 2-h infusion. Oral administrations of 600mg q12h were assessed, considering original and higher plasma protein binding. Lefamulin displayed similar PK characteristics in both Chinese and Western populations. The PopPK model effectively predicted lefamulin concentrations in Chinese CABP patients. Under the dosage regimen of 150mg q12h via intravenous infusion for 1/1.5/2h, the probability of target attainments reached 98% at the minimum inhibitory concentration for both 90% S. pneumoniae and S. aureus, considering both original and higher protein binding rates. It is advisable to extend the infusion duration from 1/1.5 h-2h to minimize the risk of adverse effects at the infusion site. Regardless of fasted or fed conditions, the PTAs for 600mg q12h lefamulin via oral administration proved comparable to those for intravenous administration. This study proved that intravenous and oral administrations of lefamulin can reach preclinical PK/PD targets of S. pneumoniae and S. aureus. These findings support the optimal use of lefamulin for the safe and effective treatment of Chinese CABP patients.

Cervical ripening with a double balloon device for 6 h in patients with a long cervix: Secondary analysis of a randomized controlled trial.

To examine whether cervical ripening with a double balloon device for 6 h is as effective as 12 h in patients with a cervical length ≥ 30 mm measured on transvaginal ultrasound before induction of labor, and to determine whether patients with a long cervix need to have the balloon placed for a longer time. This is a secondary analysis of data from a randomized controlled trial that compared maternal and neonatal outcomes between women undergoing cervical ripening with a double balloon device for 6 h (study group) versus 12 h (control group). In this secondary analysis, we included only patients who had cervical length ≥ 30 mm measured on transvaginal ultrasound on admission. Our primary outcome was a Bishop score change after removal of the device. Secondary outcomes included insertion to delivery interval, mode of delivery, and oxytocin infusion duration. Sixty-seven women met the inclusion criteria and were included in the analysis: 33 in the 6-h group and 34 in the 12-h group. Maternal characteristics were similar between both groups. Bishop score difference between the preinsertion and the postremoval scores were similar in the two groups (2.67 ± 1.8 vs. 2.53 ± 1.69, P = 0.76), while insertion to delivery time was 10 h shorter in the 6-h group (20.95 vs. 31.21, P = 0.02; mean difference, -10.26 [95% CI, -19.0 to -1.51]). The other secondary outcomes remained similar in both groups. In women undergoing induction of labor who have a cervical length ≥ 30 mm measured on admission transvaginal ultrasound, removing a double balloon device after 6 h achieved similar Bishop score changes as removal after 12 h, but significantly reduced the time to delivery. REGISTRATION AT CLINICAL TRIALS: https://classic. gov/ct2/show/NCT03045939.

Cerebral net uptake of lactate contributes to neurological injury after experimental cardiac arrest in rabbits

During focal ischemia, neurons can use lactate as an alternative source of energy through its oxidation into pyruvate by the lactate dehydrogenase (LDH). After cardiac arrest, the neurological consequences of this phenomenon are unknown. Experimental study. Experimental laboratory. Male New-Zealand rabbits. Animals were surgically instrumented and randomly divided into five groups receiving short infusion duration of either lactate or pyruvate or a pre-cardiac arrest infusion of oxamate (an inhibitor of the lactate dehydrogenase) or injection of fluorocitrate (an inhibitor of astrocytic tricarboxylic acid), or Saline (lactate, pyruvate, Oxa, FC and Control groups, respectively). After randomization, animals were submitted to 10 min of ventricular fibrillation and subsequent resuscitation. All animals were then either followed during 4 h, for the evaluation of the cerebral net uptake and concentrations of metabolites by microdialysis (n = 6 in each experimental group, n = 12 in control group), or during 48 h for the evaluation of their neurological outcome (n = 7 in each groups and n = 14 in control group). Cardiac arrest was associated with a dramatic increase in cerebral net uptake of lactate during 120 min after resuscitation, which was increased by lactate or pyruvate administration. This was associated with an increase in the mean neurological dysfunction score (66.7 ± 4.7, 79.0 ± 4.5 vs 57.7 ± 1.5 in Lactate, Pyruvate and Control group respectively) at 48 h after cardiac arrest. Oxamate and FC administration were associated with a lower lactate cerebral uptake after cardiac arrest and with an improvement of the neurological recovery (28.85 ± 9.4, 23.86 ± 6.2 vs 57.7 ± 1.5 in Oxa, FC and Control group respectively). After cardiac arrest, immediate isotonic lactate or pyruvate administration is deleterious. Pre-cardiac arrest LDH inhibition was potently neuroprotective in this setting.

Role of a Home-visit Nursing Agency in Supporting Patients with Heart Failure on Continuous Catecholamine Infusion: A Case Series Study.

This study aimed to discuss the role of home-visit nurses in managing continuous catecholamine infusion in patients with heart failure by investigating the outcome of patients and the home-visit nursing intervention. We conducted a retrospective, case series study of eight patients with heart failure who underwent home-based continuous catecholamine infusion between April 2016 and March 2024. Data including the patients' demographics, the duration of continuous catecholamine infusion, the frequency of nursing and emergency nursing visits, and patients' endpoints were collected. The median age of the patients was 68.5 (interquartile range: 51.8-80.0) years and 75% were men. The most common diagnosis requiring home-based catecholamine infusion was dilated cardiomyopathy. The median duration of continuous catecholamine infusion in the patients was 58.0 days. The median frequency of nursing visits was 8.4 times each week. Forty-five emergency nursing visits occurred, and the most common reason for these visits was managing infusion device malfunctions. Among the patients, six died at home, one was hospitalized owing to fatal arrhythmia, and one withdrew from continuous catecholamine infusion. This study shows the complexities of providing home-based care for patients with heart failure requiring continuous catecholamine infusion. Most patients with heart failure were able to spend the rest of their lives at home, despite the challenges of managing such a treatment outside the hospital. Our findings indicate the need for early intervention, multidisciplinary collaboration, and the development of home care protocols to optimize treatment efficacy and the quality of life of these patients.

Activity Assessment of Factor Replacement Therapies to Guide Infusion Rate Protocols in Patients with Bleeding Disorders

Abstract Introduction The development of institutional protocols guiding administration of clotting factor replacements in patients with bleeding disorders requires an understanding of product stability over infusion duration. Inclusion of new factor products on formulary at our institution raised consideration for optimal administration routes, including whether a bolus intravenous push versus infusion over 4-12h provided acceptable factor activities. Here we assessed the activity of two clotting factor replacement therapies over a 24h period to guide clinical care protocols. Method This study was performed in the Special Coagulation Lab as a collaboration between pharmacy, hematology, and laboratory medicine. Two vials each of Novoeight, a recombinant antihemophilic factor used in patients with factor VIII deficiency, and Vonvendi, a recombinant von Willebrand Factor (VWF) replacement approved for prophylaxis in adults with Type 3 von Willebrand Disease, were reconstituted to clinically relevant potencies (13 IU/ml, Novoeight; 27 IU/ml, Vonvendi). Products were spiked separately into factor VIII-deficient plasma (Novoeight) or assay diluent (Vonvendi), given inability to obtain VWF-deficient plasma, and tested for activity at various timepoints. Novoeight samples were assessed by traditional one-stage FVIII assays, while Vonvendi samples were assessed for VWF antigen, ristocetin cofactor activity (RCA), and glycoprotein Ib binding activity (GP1bM). Results Novoeight samples maintained similar FVIII activities at all timepoints tested, with differences falling within the coefficient of variation of the assay. Specifically, the two samples had FVIII levels of 108% and 95% at baseline and levels of 98% and 91%, respectively, at 12h, which was the timepoint of greatest interest given plans to allow 12h infusion rates. For Vonvendi samples, measurement of VWF antigen remained fairly stable throughout the 24h period. However, VWF activity decreased in both RCA and GP1bM assays over time, including by 4h. RCA values were 193% and 190% at baseline, 113% and 95% at 4h, and 63% and 63% at 12h. GP1bM was 140% and 133% at baseline, 92% and 91% at 4h, and 56% and 70% at 12h. Together, these results supported implementation of protocols allowing for extended (up to 12h) infusion of Novoeight and short (3-5min) bolus infusion of Vonvendi. Conclusion Our study demonstrated maintained Novoeight activity over the study period, confirming infusion rates of 12h should be efficacious. Conversely, Vonvendi yielded significantly decreased activity levels in as little as 4h, indicating the need for faster infusion rates. Based on our results, current practices at our institution were adapted to include extended infusion for Novoeight only. Drug activity studies may not directly reflect patient outcomes, and additional studies of factor activities following product infusion into patients and clinical hemostasis correlates are necessary. Nevertheless, the clinical lab should continue to play a primary role in testing, monitoring, and developing patient care protocols for therapeutic drugs through multidisciplinary collaboration.

Phase I clinical trial evaluating the safety, tolerance, pharmacokinetics and pharmacodynamics of HSK21542 injection in healthy volunteers.

HSK21542 injection is a new peripheral kappa opioid receptor (KOR) agonist. To evaluate its safety, tolerability, pharmacokinetics and pharmacodynamics, this study was conducted in healthy volunteers, consisting of two parts: a single ascending dose (0.2-3.375 μg/kg, 15-min infusion) and different infusion durations (0.2 and 1μg/kg, 2- or 15-min infusion). The area under the plasma concentration-time curve (AUC) and peak concentration (Cmax) of HSK21542 were dose-linear among 0.2-3.375 μg/kg. After intravenous injection, HSK21542 was rapidly eliminated with a half-life (t1/2) of 1.5h, and the majority (48.02%) of the dose was excreted unchanged in urine. Pharmacodynamic results showed that HSK21542 increased prolactin release and reached a peak at 1-2h after administration but had no significant effect on vasopressin levels. There was a brief increase in urine volume within the initial 2h after administration. HSK21542 was well tolerated; most of the adverse effects (AEs) in the trial group were grade 1, and only 2 cases (4.0%) were grade 2. The main AE was paresthesia, which appeared in 42% (21/50) in the trial group. No serious adverse event (SAE) was observed. No subject withdrew early due to AEs. These results suggest that HSK21542 may be a potential treatment for pain and pruritic conditions.

6844 Comparison of Lactated Ringers and Normal Saline in the Treatment of Diabetic Ketoacidosis

Abstract Disclosure: J.N. Johnson: None. A.T. Drincic: None. K. Nein: None. E. Buddenhagen: None. K. Samson: None. T. Langenhan: None. Background: Current guidelines recommend normal saline (NS) for fluid resuscitation in the management of patients presenting with diabetic ketoacidosis (DKA). However, previous prospective studies have demonstrated improvement in patient specific outcomes, including time to DKA resolution, when balanced crystalloid fluids are used. We hypothesized that the use of LR compared to NS for volume management in DKA will shorten time to DKA resolution, reduce time to DKA associated protocol insulin infusion discontinuation, and result in lower post-intravenous fluid resuscitation chloride values. Methods: We conducted a single institution, retrospective cohort study of patients admitted with the diagnosis of DKA following our institution’s transition from NS to lactated ringers (LR) as the default resuscitative and maintenance fluid in our DKA management protocol. Adult patients admitted with DKA before and after the protocol change were identified. The primary outcome was time from DKA clinical presentation until DKA resolution. The secondary outcome was time to discontinuation of DKA protocol continuous insulin infusion. Results: Of 246 patients meeting inclusion criteria, 119 were stratified to the NS group (pre-protocol change) and 127 to the LR group (post-protocol change). T-test analysis revealed decreased time to DKA resolution in the LR group (mean 17.1 hours; SD 11.02) relative to the NS group (mean 20.6 hours; SD 12.22; p = .02). Duration of DKA protocol continuous intravenous insulin was shorter in the LR group (mean 16.0 hours; SD 8.72) compared to the NS group (mean 21.4 hours; SD 12.50; p = 0.0001). Conclusions: In this retrospective cohort study, protocolized DKA intravenous fluid management with LR resulted in shorter time to resolution of DKA and reduced duration of DKA protocol continuous insulin infusion. Presentation: 6/2/2024

The Use of Cangrelor in Cardiogenic Shock: Insights from the CAMEO Registry

Little is known about the use of cangrelor in patients with myocardial infarction (MI) presenting with cardiogenic shock (CS). CAMEO (Cangrelor in Acute MI: Effectiveness and Outcomes) is a multicenter observational registry evaluating platelet inhibition in patients with MI. We examined the duration of cangrelor infusion and the amount of time to transition from cangrelor to an oral P2Y12 inhibitor in patients with CS. We also assessed major adverse cardiovascular events (MACEs) and bleeding risks, stratified by dosage duration, time to transition and oral P2Y12 inhibitor potency. Among 2352 cangrelor-treated patients with MI, 249 patients were in CS. Among the patients with CS, 16 (6.4%) received the "bridge" infusion dose, 202 (81.1%) the PCI cangrelor infusion dose, and 30 (12.0%) had a combination of both infusion doses. Patients with CS had a median age of 66 years; 32% were women; 21% were Black patients; 35% had diabetes; 19% received thrombectomy; and 59% received mechanical circulatory support (MCS) (35% intra-aortic balloon pump, 27% Impella). The median duration of infusion was 3.9 (2-21.5 hours) in patients with CS and was 2 (1.6-3.1 hours) for all cangrelor-treated patients. The median duration of transition from cangrelor to oral P2Y12 inhibitor administration was 0.1 (-0.5-21.0 hours) for patients with CS. In multivariable modeling, chronic lung disease and the use of MCS and was associated with longer cangrelor infusions (defined as > 3.9 hours). Among cangrelor-treated patients with CS, 24.1% of these patients had a bleeding event, and 41.8% had a MACE event. After adjustment, a longer cangrelor infusion duration was associated with increased risk of bleeding (P < 0.05). The median duration of cangrelor infusion was longer for patients presenting with CS. Use of MCS was associated with longer cangrelor infusion durations in patients with CS. Further work is needed to understand the pharmacodynamics of antiplatelet agents in patients with CS.

Evaluation of Dexmedetomidine Withdrawal and Management After Prolonged Infusion

Dexmedetomidine is often used for longer than its labeled indication of 24 hours, raising concerns for potential withdrawal. Data are limited regarding this syndrome in adult patients. This study aimed to further characterize dexmedetomidine withdrawal in critically ill adult patients after prolonged use. This was an institutional review board-approved, single-center, retrospective chart review conducted at a tertiary academic medical center. Adult intensive care unit (ICU) patients on dexmedetomidine for ≥72 hours in 2019 were screened for inclusion. Exclusion criteria were interruption of dexmedetomidine for >6 hours, indications for dexmedetomidine other than sedation, or patients with neurological or burn injury. The major end point was the incidence of dexmedetomidine withdrawal, defined as meeting ≥2 of the following criteria within 24 hours of discontinuation: newly positive Confusion Assessment Method for ICU, Richmond Agitation Sedation Scale score of ≥+2, hypertension, and tachycardia. Minor end points were incidence of individual withdrawal signs as previously described, additional sedatives or antipsychotics required, dose and duration of dexmedetomidine infusion, length of ventilation, ICU and hospital length of stay, and new onset of the following: fever, vomiting, loose stools/diarrhea, diaphoresis, or seizure. Of the 152 patients included, dexmedetomidine withdrawal occurred in 54 patients (35.5%). Rebound hypertension was the most common withdrawal sign (47 patients [87.0%]). In the withdrawal group, significantly more patients required additional β-blockers (29 [53.7%] vs 10 [10.2%]; P < 0.01), were reinitiated on dexmedetomidine (16 [29.6%] vs 10 [10.2%]; P < 0.01), and required a start or increased dose of clonidine (6 [11.1%] vs 3 [3.1%]; P = 0.04). There was no significant difference in the cumulative dose or duration of dexmedetomidine between the groups. Length of ventilation was longer in the withdrawal group (171 hours [83.7-280.8 hours] vs 159 hours [149.0-335.7 hours]; P < 0.01), but there was no difference in ICU or hospital length of stay. Prolonged use of dexmedetomidine was associated with withdrawal syndrome in 35.5% of patients in our study. Larger trials are needed to confirm the risk factors for dexmedetomidine withdrawal and identify measures to prevent withdrawal.

Descriptive Analysis of Dexmedetomidine's Utility in a Palliative Care Unit at the End of Life.

Context: Pain and symptom management at the end of life (EoL) can pose unique challenges, particularly when symptoms are refractory to conventional methods. Dexmedetomidine, originally approved for sedation in ventilated patients, has been demonstrated to be beneficial in pain management and palliative care settings by functioning as an alpha-2 agonist. Methods: A retrospective review of inpatient palliative care unit (IPU) records from January 2020 to December 2023 was conducted. Twenty-five adult patients receiving continuous dexmedetomidine for refractory pain at the EoL were identified. These patients were further evaluated for concurrent opioid, benzodiazepine, and chlorpromazine usage. Results: Patients experienced predominantly cancer-related pain, and had a median infusion duration of 5 days. Dexmedetomidine's initial dosing differed between the intensive care unit (ICU) and IPU settings. There was a trend toward a decreased opioid requirement 24 hours after initiation. Patients transferred from the ICU showed a progressive increase in opioid use. Conclusion: This study contributes to understanding dexmedetomidine's role in managing refractory symptoms at the EoL in the palliative care setting.

A Phase 4 Study to Evaluate the Safety and Tolerability of Higher Infusion Rates of Agalsidase Beta to Shorten Infusion Duration in Fabry Disease: Interim Analysis

A Phase 4 Study to Evaluate the Safety and Tolerability of Higher Infusion Rates of Agalsidase Beta to Shorten Infusion Duration in Fabry Disease: Interim Analysis

Influence of acepromazine on the cardiovascular effects of dobutamine in isoflurane anaesthetised horses premedicated with romifidine

ObjectiveTo explore the influence of acepromazine on the cardiovascular effects of dobutamine in isoflurane-anaesthetised horses premedicated with romifidine. Study designProspective randomised clinical trial. AnimalsA total of 18 horses undergoing elective arthroscopy were enrolled, of which 12 horses requiring dobutamine were included. Methodsorses were randomised to receive acepromazine 0.02 mg kg-1 (Group A+) intravenously (IV) or none (Group A-), 35 minutes before anaesthesia. Horses received xylazine 0.2 mg kg-1 concurrently to facilitate IV access. Horses were premedicated with romifidine 0.08 mg kg-1, induced with ketamine 2.2 mg kg-1 and diazepam 0.08 mg kg-1 IV, and maintained with isoflurane in oxygen. Dobutamine infusion was commenced when mean arterial pressure (MAP) was < 60 mmHg. Cardiovascular data were collected prior to dobutamine, and at a target MAP of ≥ 70 mmHg. Dobutamine start time from induction, duration and dose to reach target MAP were compared using Mann-Whitney U test. Cardiovascular variables were compared using repeated measures ANOVA and post-hoc Fisher’s least significant difference test. ResultsCardiac index (CI) and its percentage change was significantly higher at target MAP in group A+ [42.8 (17.0–68.7) %] than in A- [-4.05 (-21.2–13.0) %] (p = 0.003). Group A+ required significantly earlier dobutamine [20 (18–25) minutes] than group A- [36 (27–60) minutes] (p = 0.02). Group A+ required significantly higher dobutamine dose [1.5 (1–2.5) μg kg-1 minute-1] to reach target MAP than group A- [0.5 (0.5–1) μg kg-1 minute-1] (p = 0.009). No significant difference in infusion duration to reach target MAP was found between groups. Conclusion and clinical relevanceDobutamine significantly increased MAP and CI following pre-anaesthetic acepromazine sedation, in isoflurane-anaesthetised horses premedicated with romifidine. Without acepromazine, dobutamine increased MAP but not CI. Interactions between acepromazine, romifidine and dobutamine on the cardiovascular system should be considered.