Intraperitoneal chemotherapy for peritoneal metastases of gastric origin: a systematic review and meta-analysis.

BACKGROUND: Gastric cancer with peritoneal metastases is associated with a dismal prognosis. Normothermic catheter-based intraperitoneal chemotherapy and normothermic pressurized intraperitoneal aerosol chemotherapy (PIPAC) are methods to deliver chemotherapy intraperitoneally leading to higher intraperitoneal concentrations of cytotoxic drugs compared to intravenous administration. We reviewed the effectiveness and safety of different methods of palliative intraperitoneal chemotherapy. METHODS: Embase, MEDLINE, Web of Science and Cochrane were searched for articles studying the use of repeated administration of palliative intraperitoneal chemotherapy in patients with gastric cancer and peritoneal metastases, published up to January 2024. The primary outcome was overall survival. RESULTS: Twenty-three studies were included, representing a total of 999 patients. The pooled median overall survival was 14.5 months. The pooled hazard ratio of the two RCTs using intraperitoneal paclitaxel and docetaxel favoured the intraperitoneal chemotherapy arm. The median overall survival of intraperitoneal paclitaxel, intraperitoneal docetaxel and PIPAC with cisplatin and doxorubicin were respectively 18.4 months, 13.2 months and 9.0 months. All treatment methods had a relatively safe toxicity profile. Conversion surgery after completion of intraperitoneal therapy was performed in 16% of the patients. CONCLUSIONS: Repeated intraperitoneal chemotherapy, regardless of method of administration, is safe for patients with gastric cancer and peritoneal metastases. Conversion surgery after completion of the intraperitoneal chemotherapy is possible in a subset of patients.

Sensor macrophages derived from human induced pluripotent stem cells to assess pyrogenic contaminations in parenteral drugs.

Ensuring the safety of parenteral drugs before injection into patients is of utmost importance. New regulations around the globe and the need to refrain from using animals however, have highlighted the need for new cell sources to be used in next-generation bioassays to detect the entire spectrum of possible contaminating pyrogens. Given the current drawbacks of the Monocyte-Activation-Test (MAT) with respect to the use of primary peripheral blood mono-nuclear cells or the use of monocytic cell lines, we here demonstrate the manufacturing of sensor monocytes/macrophages from human induced pluripotent stem cells (iMonoMac), which are fully defined and superior to current cell products. Using a modern and scalable manufacturing platform, iMonoMac showed typical macrophage-like morphology and stained positive for several Toll like receptor (TLRs) such as TLR-2, TLR-5, TLR-4. Furthermore, iMonoMac derived from the same donor were sensitive to endotoxins, non-endotoxins, and process related pyrogens at a high dynamic range and across different cellular densities. Of note, iMonoMac showed increased sensitivity and reactivity to a broad range of pyrogens, demonstrated by the detection of interleukin-6 at low concentrations of LPS and MALP-2 which could not be reached using the current MAT cell sources. To further advance the system, iMonoMac or genetically engineered iMonoMac with NF-κB-luciferase reporter cassette could reveal a specific activation response while correlating to the classical detection method employing enzyme-linked immunosorbent assay to measure cytokine secretion. Thus, we present a valuable cellular tool to assess parenteral drugs safety, facilitating the future acceptance and design of regulatory-approved bioassays.

Is it advantageous to use quality by design (QbD) to develop nanoparticle-based dosage forms for parenteral drug administration?

Parenteral administration is one of the most commonly used drug delivery routes for nanoparticle-based dosage forms, such as lipid-based and polymeric nanoparticles. For the treatment of various diseases, parenteral administration include intravenous, subcutaneous, and intramuscular route. In drug development phase, multiparameter strategy with a focus on drug physicochemical properties and the specificity of the administration route is required. Nanoparticle properties in terms of size and targeted delivery, among others, are able to surpass many drawbacks of conventional dosage forms, but these unique properties can be a bottleneck for approval by regulatory authorities. Quality by Design (QbD) approach has been widely utilized in development of parenteral nanoparticle-based dosage forms. It fosters knowledge of product and process quality by involving sound scientific data and risk assessment strategies. A full and comprehensive investigation into the state of implementation and applications of the QbD approach in these complex drug products can highlight the gaps and challenges. In this review, the analysis of critical attributes and Design of Experiment (DoE) approach in different nanoparticulate systems, together with the proper utilization of Process Analytical Technology (PAT) applications are described. The essential of QbD approach for the design and development of nanoparticle-based dosage forms for delivery via parenteral routes is discussed thoroughly.

Combination of Parenteral Amino Acid Infusion and Intermittent Loading Exercise Ameliorates Progression of Postoperative Sarcopenia in Rat Model.

Postoperative sarcopenia is associated with poor outcomes in hospitalized patients. However, few studies have focused on short-term postoperative sarcopenia. Furthermore, the influence of nutritional management using amino acids (AAs) comprising a peripheral parenteral nutrition (PPN) solution and its combination with exercise (Exc) is unclear. Hence, we established a postoperative sarcopenic rat model to evaluate the effects of parenteral AA infusion combined with Exc on skeletal muscles and investigate the underlying mechanisms involved in the amelioration of muscle atrophy. Male F344 rats underwent surgery followed by hindlimb suspension (HS) for 5 days. The rats were divided into AA (-), AA (+), AA (-)-Exc, and AA (+)-Exc groups. They were continuously administered a PPN solution with or without AA at 98 kcal/kg/day. The Exc groups were subjected to intermittent loading for 1 h per day. Postoperative sarcopenic rats exhibited decreased muscle strength and mass and an upregulated ubiquitin-proteasome system, autophagy-lysosome system, and fast-twitch fiber-related genes, especially in the AA (-) group. The AA (+)-Exc group exhibited attenuated decreased muscle strength, increased gastrocnemius mass, and a suppressed upregulation of muscle atrophy- and fast-twitch fiber-related genes. Therefore, parenteral AA infusion combined with Exc may be effective in preventing postoperative sarcopenia in hospitalized patients.

Exploring patients' perspectives: a mixed methods study on Outpatient Parenteral Antimicrobial Therapy (OPAT) experiences.

BACKGROUND: Outpatient Parenteral Antimicrobial Therapy (OPAT), an alternative to inpatient intravenous antibiotic therapy, has shown benefits in international studies such as increased patient satisfaction. Because OPAT has been used only sporadically in Germany so far, no structured results on patients' experiences and concerns regarding OPAT have yet been available. This study therefore aims to explore the experiences of OPAT patients in a pilot region in Germany. METHODS: This is an observational study in a German pilot region, including a survey of 58 patients on their experiences with OPAT, and in-depth interviews with 12 patients (explanatory-sequential mixed-methods design). RESULTS: Patients reported that they were satisfied with OPAT. That a hospital discharge was possible and anti-infective therapy could be continued in the home environment was rated as being particularly positive. In the beginning, many patients in the interviews were unsure about being able to administer the antibiotic therapy at home on their own. However, healthcare providers (doctors and pharmacy service provider staff) were able to allay these concerns. Patients appreciated regular contact with care providers. There were suggestions for improvement, particularly concerning the organization of the weekly check-up appointments and the provision of information about OPAT. CONCLUSIONS: Patients were generally satisfied with OPAT. However, the treatment structures in Germany still need to be expanded to ensure comprehensive and high-quality OPAT care. TRIAL REGISTRATION: NCT04002453, https://www. CLINICALTRIALS: gov/ , (registration date: 2019-06-21).

Standardizing eligibility and patient selection for Pressurized Intraperitoneal Aerosol Chemotherapy: A Delphi consensus statement.

INTRODUCTION: Pressurized Intraperitoneal Aerosol Chemotherapy (PIPAC) is a procedure for minimally invasive drug administration in patients with peritoneal metastasis. Previous studies have emphasized the importance of uniformity in treatment protocols and standardization of this practice. This study aimed to reach a consensus on eligibility, patient selection, and choice of chemotherapy for PIPAC. METHODS: A three-round modified Delphi study was conducted. A steering group formulated a list of baseline statements, addressing the objectives. The steering group consisted of seven expert surgical and medical oncologists. Available evidence and published key opinions were critically reviewed. An international expert panel scored those statements on a 4-point Likert scale. The statements were submitted electronically and anonymously. Consensus was reached if the agreement rate was ≥75%. A minimum Cronbach's alpha of >0.8 was set. RESULTS: Forty-five (45/58; 77.6%) experts participated and completed all rounds. Experts were digestive surgeons (n = 28), surgical oncologists (n = 7), gynecologists (n = 5), medical oncologists (n = 4), and one clinical researcher. Their assessment of 81 preliminary statements in the first round resulted in 41 consolidated statements. In round two, consensus was reached on 40 statements (40/41; 97.6%) with a consensus of ≥80% for each individual statement. In the third round, 40 statements were unanimously approved as definitive. The choice of first- and second-line chemotherapy remained controversial and could not reach consensus. CONCLUSIONS: This International Delphi study provides practical guidance on eligibility and patient selection for PIPAC. Ongoing trial data and long-term results that could contribute to the further standardization of PIPAC are eagerly awaited.

Implementation of Infusion Pumps and Filtered Administration Sets for Stem Cell Transplantation.

Stem cell infusion practices vary widely among institutions. A nurse-driven quality improvement project sought to determine whether peristaltic pumps and filtered tubing compromised the safety of stem cell infusion. A preclin.

Barriers and facilitators for the implementation and expansion of outpatient parenteral antimicrobial therapy: a systematic review.

Outpatient parenteral antimicrobial therapy (OPAT) has been expanding in recent years and serves as a viable solution in reducing the shortage of hospital beds. However, the wider implementation of OPAT faces numerous challenges. This review aimed to assess implementation barriers and facilitators of OPAT services. Studies describing barriers and facilitators of the OPAT service were retrieved from PubMed, Scopus, MEDLINE, EMBASE, CINAHL, Cochrane Library, Web of Science Proceedings, International Pharmaceutical Abstracts and PsycINFO. All types of study designs published in the English language were included. Studies that did not mention any barrier or facilitator, did not differentiate OPAT and inpatient, focused on specific antimicrobials or diseases, and made no distinction between parenteral and other treatments were excluded. Qualitative analysis was performed using the 'best-fit' framework approach and the Consolidated Framework for Implementation Research (CFIR). The review was PROSPERO registered (CRD42023441083). A total of 8761 studies were screened for eligibility and 147 studies were included. Problems in patient selection, lack of awareness, poor communication and co-ordination, lack of support, lack of structured service and inappropriate prescriptions were identified. OPAT provides safe, effective and efficient treatment while maintaining patients' privacy and comfort, resulting in less daily life disruption, and reducing the risk of infection. Satisfaction and preference for OPAT were very high. Initiatives in strengthening OPAT such as antimicrobial stewardship and telemedicine are beneficial. Challenges to and facilitators of OPAT were identified among patients, health professionals, OPAT service providers and healthcare administrators. Understanding them is crucial to designing targeted initiatives for successful OPAT service implementation.

The effect of an initial catheter ablation with an adjunctive ethanol infusion into the vein of Marshall on persistent atrial fibrillation.

INTRODUCTION: Some previous studies have reported that a first-step ethanol infusion into the vein of Marshall (EIVOM) with touch-up radiofrequency (RF) ablation can facilitate mitral isthmus (MI) block and improves the ablation outcomes in persistent atrial fibrillation (PeAF) patients. However, the effect of an initial RF ablation with an adjunctive EIVOM has not been fully investigated. METHODS: This study enrolled 233 PeAF patients undergoing pulmonary vein isolation and linear ablation including an MI, roof line, and cavotricuspid isthmus ablation. An EIVOM was performed when endocardial ablation with or without coronary sinus ablation failed to create MI block. RESULTS: Bidirectional MI block was achieved in 224 patients (96.1%). Among them, MI block was obtained by only RF ablation in 174/224 patients (77.7%) (RF group) and an adjunctive EIVOM was needed in 50/224 (22.3%) (EIVOM group). During the follow-up, 113 (64.9%) RF group patients were free from AF/atrial tachycardia compared to 41 (82.0%) EIVOM group patients (log-rank p = .045). In a multivariate Cox regression analysis, an adjunctive EIVOM was associated with a lower recurrence rate (hazard ratio = 0.39, 95% confidence interval = 0.17-0.78, p = .006). CONCLUSION: An initial RF ablation with an adjunctive EIVOM strategy improved MI ablation's acute success rate and was associated with better clinical outcomes.

Experiencia de la administración de hierro endovenoso en hospitalización a domicilio mediante elastómeros / Experience of the administration of intravenous iron in hospitalization at home using elastomers

Objetivo: analizar las características clínicas y demográficas de las personas atendidas por la unidad de hospitalización a domicilio (HAD) que recibieron tratamiento de hierro endovenoso en perfusión por bomba elastomérica. Estudio retrospectivo desde enero del 2022 a noviembre del 2023.En total se administró hierro endovenoso con bomba elastomérica en el domicilio a un total de 53 personas siendo estas en un 74% pacientes crónicos complejos o pacientes con enferme-dad crónica avanzada. Ninguna de las personas a las que se les administró el tratamiento de hierro endovenoso presentaron reacciones adversas. Por ello, la administración de hierro endovenoso en el domicilio por el HAD supone una práctica eficaz y segura mejora la calidad de vida de las personas usuarias y su entorno familiar (AU)

Objective: to analyze the clinical and demographic characteristics of the people treated by the home hospitalization unit (HAD) who received intravenous iron treatment in infusion by elastomeric pump. Retrospective study from January 2022 to November 2023. In total, intravenous iron was administered with an elastomeric pump at home to a total of 53 people, 74% of whom were complex chronic patients or patients with advanced chronic disease. None of the people who were administered intravenous iron treatment had adverse reactions.This is why the administration of intravenous iron at home by the HAD is an effective and safe practice and improves the quality of life of users and their family environment. (AU)

Hospital Prices for Physician-Administered Drugs for Patients with Private Insurance.

BACKGROUND: Hospitals can leverage their position between the ultimate buyers and sellers of drugs to retain a substantial share of insurer pharmaceutical expenditures. METHODS: In this study, we used 2020-2021 national Blue Cross Blue Shield claims data regarding patients in the United States who had drug-infusion visits for oncologic conditions, inflammatory conditions, or blood-cell deficiency disorders. Markups of the reimbursement prices were measured in terms of amounts paid by Blue Cross Blue Shield plans to hospitals and physician practices relative to the amounts paid by these providers to drug manufacturers. Acquisition-price reductions in hospital payments to drug manufacturers were measured in terms of discounts under the federal 340B Drug Pricing Program. We estimated the percentage of Blue Cross Blue Shield drug spending that was received by drug manufacturers and the percentage retained by provider organizations. RESULTS: The study included 404,443 patients in the United States who had 4,727,189 drug-infusion visits. The median price markup (defined as the ratio of the reimbursement price to the acquisition price) for hospitals eligible for 340B discounts was 3.08 (interquartile range, 1.87 to 6.38). After adjustment for drug, patient, and geographic factors, price markups at hospitals eligible for 340B discounts were 6.59 times (95% confidence interval [CI], 6.02 to 7.16) as high as those in independent physician practices, and price markups at noneligible hospitals were 4.34 times (95% CI, 3.77 to 4.90) as high as those in physician practices. Hospitals eligible for 340B discounts retained 64.3% of insurer drug expenditures, whereas hospitals not eligible for 340B discounts retained 44.8% and independent physician practices retained 19.1%. CONCLUSIONS: This study showed that hospitals imposed large price markups and retained a substantial share of total insurer spending on physician-administered drugs for patients with private insurance. The effects were especially large for hospitals eligible for discounts under the federal 340B Drug Pricing Program on acquisition costs paid to manufacturers. (Funded by Arnold Ventures and the National Institute for Health Care Management.).

Extended physicochemical stability of cetuximab in opened vials and infusion bags when stored at 4°C and 25°C.

INTRODUCTION: This study aimed to determine the stability of cetuximab: (1) under "in-use" conditions after dilution to 1 mg/mL in 0.9% sodium chloride in polyolefin bags and (2) as an undiluted solution (5 mg/mL) repackaged in polypropylene bags or kept in the vial after opening. METHODS: Ready-to-use 500 mg/100 mL vials of cetuximab solution were diluted to 1 mg/mL in 100 mL bags of 0.9% sodium chloride or repackaged as a 5 mg/mL solution into empty 100 mL bags. Bags and vials were stored at 4°C for 90 days and 25°C for 3 days. A syringe sample of 7 mL was taken from each bag for the initial determinations. The sampled bags were weighed to determine their initial weight and placed under the planned storage conditions. The physicochemical stability of cetuximab was estimated using validated methods. RESULTS: No changes in turbidity, no protein loss, and no changes in cetuximab tertiary structure were observed after 30 days of storage or when subjected to a temperature excursion of 3 days at 25°C and when stored at 4°C for up to 90 days, regardless of the concentrations and batches. The colligative parameters did not change under any of the tested conditions. No evidence of microbial growth was found in bags after 90 days of storage at 4°C. CONCLUSION: These results support the extended in-use shelf-life of cetuximab vials and bags, which can be cost-effective for healthcare providers.

Effect of intraperitoneal infusion of ropivacaine combined with dexmedetomidine in patients undergoing total laparoscopic hysterectomy: a single-center randomized double-blinded controlled trial.

PURPOSE: To investigate the effect of intraperitoneal infusion of ropivacaine combined with dexmedetomidine and ropivacaine alone on the quality of postoperative recovery of patients undergoing total laparoscopic hysterectomy (TLH). METHODS: Female patients scheduled to undergo a TLH under general anesthesia at Fujian Maternity and Child Health Hospital were included. Before the end of pneumoperitoneum, patients were laparoscopically administered an intraperitoneal infusion of 0.25% ropivacaine 40 ml (R group) or 0.25% ropivacaine combined with 1 µg/kg dexmedetomidine 40 ml (RD group). The primary outcome was QoR-40, which was assessed before surgery and 24 h after surgery. Secondary outcomes included postoperative NRS scores, postoperative anesthetic dosage, the time to ambulation, urinary catheter removal, and anal exhaust. The incidence of dizziness, nausea, and vomiting was also analyzed. RESULTS: A total of 109 women were recruited. The RD group had higher QoR scores than the R group at 24 h after surgery (p < 0.05). Compared with the R group, NRS scores in the RD group decreased at 2, 6, 12, and 24 h after surgery (all p < 0.05). In the RD group, the time to the first dosage of postoperative opioid was longer and the cumulative and effective times of PCA compression were less than those in the R group (all p < 0.05). Simultaneously, the time to ambulation (p = 0.033), anal exhaust (p = 0.002), and urethral catheter removal (p = 0.018) was shortened in the RD group. The RD group had a lower incidence of dizziness, nausea, and vomiting (p < 0.05). CONCLUSION: Intraperitoneal infusion of ropivacaine combined with dexmedetomidine improved the quality of recovery in patients undergoing TLH. TRIAL REGISTRATION: ChiCTR2000033209, Registration Date: May 24, 2020.

Effectiveness and safety of a disposable elastomeric continuous infusion pump for outpatient parenteral antimicrobial therapy (OPAT) in a UK setting.

We evaluated the effectiveness and safety of continuous antimicrobial infusion using a disposable elastomeric device in an outpatient parenteral antimicrobial therapy (OPAT) setting. We conducted a retrospective analysis of all patients who received either flucloxacillin (n = 131 episodes) or piperacillin/tazobactam (n = 301 episodes) as continuous infusion via elastomeric devices over 5 years (January 2018-December 2022) at a tertiary referral hospital in Derbyshire, UK. Overall, 81 adverse events were recorded in 77 (18%; 77/432) patient-episodes. Most adverse events were vascular access-related (59%; 4.6 events per 1000 OPAT-days), including one line-related infection (0.2%; 0.1 events per 1000 OPAT-days). 165 (38%) patient-episodes experienced at least one incident of incomplete infusion. Successful outcome (cure or improvement) occurred in 364 (84%) episodes. Our findings suggest that elastomeric infusion pumps are safe and effective for administering selected antimicrobial agents in OPAT. However, close monitoring of patients and the device are essential to ensure optimal delivery of prescribed therapy.

Factors associated with loss to follow-up in outpatient parenteral antimicrobial therapy: A retrospective cohort study.

We assessed factors associated with increased risk to loss of follow-up with infectious diseases staff in OPAT patients. Discharge to subacute healthcare facilities is strongly associated with loss to follow-up. We did not identify sociodemographic disparities. Poor communication between OPAT providers and subacute healthcare facilities remains a serious issue.

The effect of patient's body weight, infusion connection point, and infusion pump position on intravenous multi-infusion drug delivery at low infusion rates suitable for premature neonates.

INTRODUCTION: Parenteral drug administration in the neonatal intensive care involves complex pharmacotherapy adjusted for the patient's weight, fluid allowance, and complex multi-infusion systems. OBJECTIVES: We investigated the delivery rate of a model drug through a multi-infusion system consisting of six intravenous infusions. METHODS: Delivery rate of the model drug was determined after infusion initiation and termination. Measurements were collected spectrophotometrically in real time. Time to drug delivery and the amount of drug delivered were measured. KEY FINDINGS: The longest time to drug delivery was observed for a 500 g neonate model with a distal infusion connection point and neutral pump position (337 ± 30 min, P < 0.001). The shortest time was observed for a 1000 g neonate model in the combination of proximal infusion connection point and neutral pump position (18 ± 12 min, P < 0.05). The expected 100% of the drug was delivered only in two combinations: 500 g and 1000 g neonate models, proximal infusion connection point and neutral pump position (100.4 ± 4.7%, P = 0.819 and 100.2 ± 2.7%, P = 0.874, respectively). While the least drug was delivered to a 500 g neonate model in the combination of distal infusion connection point and neutral pump position (27.5 ± 5.8%, P < 0.001). CONCLUSIONS: Delayed drug delivery to premature neonates due to multi-infusion systems may compromise accurate drug administration and lead to dosing errors.

Impact of the Design of Different Infusion Containers on the Dosing Accuracy of a Therapeutic Drug Product.

Residual volumes of infusion solutions vary greatly due to container and dimensional variances. Manufacturers use overfill to compensate, but the exact amounts vary significantly. This variability in overfill - when carrier solutions are used to dilute other parenteral preparations - may lead to variable concentrations and dosing, hence, potential risk for patients. We analyzed the overfill and residual volume of 22 pre-filled infusion containers and evaluated the impact on the (simulated) dosing accuracy of a therapeutic drug product for different handling scenarios. In addition, compendial properties of the diluents (i.e. sub-visible particles, pH, color and opalescence) were assessed. The overfill and residual volume between different containers for the same diluent varied. As container size increased, the relative volume of overfill decreased while the residual volume remained constant. The design and material of the containers (e.g. port systems) defined the residual volume. Different handling scenarios led to differences in dosing accuracy. As a result, no universal approach applicable for all containers can be defined. To ensure the right dose, it is recommended to pre-select the preferred diluent, evaluate fill volumes of carrier solutions, and assess in-use compatibility of the product solution with its diluent in terms of concentration and volume.

Population pharmacokinetic/pharmacodynamic modeling and exposure-response analysis of ciprofol in the induction and maintenance of general anesthesia in patients undergoing elective surgery: A prospective dose optimization study.

AIM: This study aimed to establish a population pharmacokinetic and pharmacodynamic (PK-PD) model to explore the optimal maintenance dose and appropriate starting time of maintenance dose after induction of ciprofol and investigate the efficacy and safety of ciprofol for general anesthesia induction and maintenance in patients undergoing elective surgery. METHOD: A total of 334 subjects with 3092 concentration measurements from nine clinical trials and 115 subjects with 5640 bispectral index (BIS) measurements from two clinical trials were used in the population PK-PD analysis. Exposure-response relationships for both efficacy endpoints (duration of anesthesia successful induction, time to recovery from anesthesia, time to respiratory recovery, and time from discontinuation to the 1st/3rd consecutive Aldrete score ≥ 9) and safety variables (hypotension, bradycardia, and injection site pain) were evaluated based on the data gathered from 115 subjects in two clinical trials. RESULT: Ciprofol pharmacokinetics (PK) were adequately described by a three-compartment model with first-order elimination from the central compartment and redistribution from the deep and shallow peripheral compartments. An inhibitory sigmoidal Emax model best described the relationship between ciprofol effect-site concentrations and BIS measurements. Body weight, age, sex, blood sampling site, and study type (short-term infusion vs long-term infusion) were identified as statistically significant covariates on the PK of ciprofol. No covariates were found to have a significant effect on the pharmacodynamic (PD) parameters. The PK-PD simulation results showed that the optimal maintenance dose was 0.8 mg/kg/h and the appropriate time to start the maintenance dose was 4-5 mins after the induction dose of ciprofol. Within the exposure range of this study, no meaningful correlations between ciprofol exposures and efficacy or safety endpoints were observed. CONCLUSION: A population PK-PD model was successfully developed to describe the ciprofol PK and BIS changes. Efficacy was consistent across the exposure range with a well-tolerated safety profile indicating no maintenance dose adjustment is required for patients undergoing elective surgery.