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Experimental Physiology May 2024Endotoxin administration is commonly used to study the inflammatory response, and though traditionally given as a bolus injection, it can be administered as a continuous...
Endotoxin administration is commonly used to study the inflammatory response, and though traditionally given as a bolus injection, it can be administered as a continuous infusion over multiple hours. Several studies hypothesize that the latter better represents the prolonged and pronounced inflammation observed in conditions like sepsis. Yet very few experimental studies have administered endotoxin using both strategies, leaving significant gaps in determining the underlying mechanisms responsible for their differing immune responses. We used mathematical modelling to analyse cytokine data from two studies administering a 2 ng kg dose of endotoxin, one as a bolus and the other as a continuous infusion over 4 h. Using our model, we simulated the dynamics of mean and subject-specific cytokine responses as well as the response to long-term endotoxin administration. Cytokine measurements revealed that the bolus injection led to significantly higher peaks for interleukin (IL)-8, while IL-10 reaches higher peaks during continuous administration. Moreover, the peak timing of all measured cytokines occurred later with continuous infusion. We identified three model parameters that significantly differed between the two administration methods. Monocyte activation of IL-10 was greater during the continuous infusion, while tumour necrosis factor and IL-8 recovery rates were faster for the bolus injection. This suggests that a continuous infusion elicits a stronger, longer-lasting systemic reaction through increased stimulation of monocyte anti-inflammatory mediator production and decreased recovery of pro-inflammatory catalysts. Furthermore, the continuous infusion model exhibited prolonged inflammation with recurrent peaks resolving within 2 days during long-term (20-32 h) endotoxin administration.
Topics: Humans; Endotoxins; Cytokines; Male; Inflammation; Interleukin-10; Models, Theoretical; Infusions, Intravenous; Monocytes; Interleukin-8; Tumor Necrosis Factor-alpha; Adult; Female; Lipopolysaccharides
PubMed: 38466166
DOI: 10.1113/EP091552 -
The Journal of Thoracic and... Aug 2010Cefazolin (1-2 g bolus at induction possibly repeated after cardiopulmonary bypass) remains the standard for antibiotic prophylaxis in cardiac surgery. Data indicate,... (Comparative Study)
Comparative Study Randomized Controlled Trial
OBJECTIVE
Cefazolin (1-2 g bolus at induction possibly repeated after cardiopulmonary bypass) remains the standard for antibiotic prophylaxis in cardiac surgery. Data indicate, however, that it is underdosed with this dosing schedule. A prospective, randomized study comparing intermittent versus loading dose plus continuous infusion for the same total dose of cefazolin was performed to assess which modality is pharmacokinetically and pharmacodynamically advantageous.
METHODS
Patients received 2 g cefazolin as a starting dose and then were divided into an intermittent group (receiving another 1 g at 3, 9, and 15 hours after the first dose) and a continuous group (continuous infusion started after the first dose, providing 1 g every 6 hours for 18 hours). Cefazolin levels were measured in blood and atria.
RESULTS
Mean total and calculated free trough concentrations in blood varied greatly among patients in the intermittent group and were lower than those in the continuous group (P < .05 at 15, 18 and 24 hours). For 9 of 10 (90%) patients in the continuous infusion group, the targeted pharmacokinetic and pharmacodynamic goal (time above minimal inhibitory concentration >90%) was achieved, whereas the goal was met for only 3 of 10 (30%) in the intermittent group (P < .05). The mean atrial tissue concentration was also higher with continuous infusion (P < .05).
CONCLUSIONS
Administration of cefazolin as bolus plus continuous infusion has pharmacokinetic and pharmacodynamic advantages relative to intermittent administration. It provides more stable serum levels, lower interpatient variability, and higher myocardial tissue penetration.
Topics: Aged; Anti-Bacterial Agents; Antibiotic Prophylaxis; Cardiac Surgical Procedures; Cefazolin; Drug Administration Schedule; Elective Surgical Procedures; Female; Humans; Infusions, Intravenous; Injections, Intravenous; Male; Middle Aged; Myocardium; Prospective Studies; Surgical Wound Infection; Treatment Outcome
PubMed: 20570290
DOI: 10.1016/j.jtcvs.2010.03.038 -
British Journal of Anaesthesia Jan 1996We have studied the pharmacokinetics of a single bolus of rocuronium (Org 9426), followed by an infusion, in eight patients during anaesthesia with halothane and nitrous...
We have studied the pharmacokinetics of a single bolus of rocuronium (Org 9426), followed by an infusion, in eight patients during anaesthesia with halothane and nitrous oxide in oxygen. Neuromuscular block was monitored using train-of-four (TOF) stimulation and recording the force of contraction of the adductor pollicis muscle. Rocuronium was administered as an initial bolus dose of 0.45 mg kg-1 followed by an infusion adjusted manually to maintain T1 (first response in the TOF) at 10% of control. Mean onset time and time to recovery of T1 to 10% were 72 (SD 19.6) s and 27 (9.6) min, respectively. The infusion rates were stable in 19.8 (6.5) min. The mean requirement for rocuronium for steady state 90% block of T1 was 528 (163.3) micrograms kg-1 h-1. After cessation of surgery the infusion was stopped and patients were allowed to recover spontaneously. The times to attain a T1 of 90% and a TOF ratio of 0.7 were 31 (11.7) min and 36 (7.3) min, respectively. Blood samples were collected for 390 min after cessation of infusion and concentrations of rocuronium and its putative metabolites measured using HPLC. A two-exponential equation was used to describe the pharmacokinetic data. The rate of clearance, mean residence time and volume of distribution at steady state were 3.3 (0.77) ml kg-1 min-1, 67.2 (18.8) min and 212.5 (40.1) ml kg-1, respectively. The distribution (T1/2 alpha) and elimination (T1/2 beta) half-lives were 7.5 (3.33) min and 85.6 (18.4) min, respectively. These values were not significantly different from previously published data for a single bolus dose of rocuronium.
Topics: Adolescent; Adult; Androstanols; Anesthesia, Inhalation; Anesthetics, Inhalation; Female; Halothane; Humans; Infusions, Intravenous; Male; Middle Aged; Muscle Contraction; Neuromuscular Junction; Neuromuscular Nondepolarizing Agents; Rocuronium
PubMed: 8672375
DOI: 10.1093/bja/76.1.29 -
British Journal of Anaesthesia May 2017Carbetocin is a synthetic oxytocin-analogue, which should be administered as bolus according to manufacturer's recommendations. A higher speed of oxytocin administration... (Comparative Study)
Comparative Study Randomized Controlled Trial
Efficacy and safety of carbetocin given as an intravenous bolus compared with short infusion for Caesarean section - double-blind, double-dummy, randomized controlled non-inferiority trial.
BACKGROUND
Carbetocin is a synthetic oxytocin-analogue, which should be administered as bolus according to manufacturer's recommendations. A higher speed of oxytocin administration leads to increased cardiovascular side-effects. It is unclear whether carbetocin administration as short infusion has the same efficacy on uterine tone compared with bolus administration and whether haemodynamic parameters differ.
METHODS
In this randomized, double-blind, non-inferiority trial, women undergoing planned or unplanned Caesarean section (CS) under regional anaesthesia received a bolus and a short infusion, only one of which contained carbetocin 100 mcg (double dummy). Obstetricians quantified uterine tone two, three, five and 10 min after cord-clamping by manual palpation using a linear analogue scale from 0 to 100. We evaluated whether the lower limit of the 95% CI of the difference in maximum uterine tone within the first five min after cord-clamping did not include the pre-specified non-inferiority limit of -10.
RESULTS
Between December 2014 and November 2015, 69 patients were randomized to receive carbetocin as bolus and 71 to receive it as short infusion. Maximal uterine tone was 89 in the bolus and 88 in the short infusion group (mean difference -1.3, 95% CI -5.7 to 3.1). Bp, calculated blood loss, use of additional uterotonics, and side-effects were comparable.
CONCLUSIONS
Administration of carbetocin as short infusion does not compromise uterine tone and has similar cardiovascular side-effects as a slow i.v. bolus. In accordance with current recommendations for oxytocin, carbetocin can safely be administered as short -infusion during planned or unplanned CS.
CLINICAL TRIAL REGISTRATION
ClinicalTrials.gov NCT02221531 and www.kofam.ch SNCTP000001197.
Topics: Adult; Cesarean Section; Double-Blind Method; Female; Hemodynamics; Humans; Infusions, Intravenous; Injections, Intravenous; Oxytocics; Oxytocin; Postpartum Hemorrhage; Pregnancy; Treatment Outcome; Uterine Contraction
PubMed: 28498927
DOI: 10.1093/bja/aex034 -
British Journal of Anaesthesia May 1989Mivacurium chloride is a new, short-acting nondepolarizing neuromuscular blocking agent presently undergoing clinical evaluation. The neuromuscular effects of mivacurium... (Clinical Trial)
Clinical Trial Comparative Study Randomized Controlled Trial
Mivacurium chloride is a new, short-acting nondepolarizing neuromuscular blocking agent presently undergoing clinical evaluation. The neuromuscular effects of mivacurium and suxamethonium given by bolus and infusion were compared in adult patients during nitrous oxide-oxygen-opioid anaesthesia. Neuromuscular block was monitored by recording the compound electromyogram of the adductor pollicis muscle resulting from supramaximal train-of-four stimuli applied to the ulnar nerve. Time to onset of complete block and recovery to T5 were significantly shorter for suxamethonium than for mivacurium (1.0 (0.1) v. 2.5 (0.3) min and 6.4 (0.7) v. 17.5 (1.8) min; mean (SEM]. Conditions for tracheal intubation were similar in the two groups although intubation was performed 0.75-1.3 min later following mivacurium. The infusion rate required to maintain neuromuscular block was 88.6 (10.4) micrograms kg-1 min-1 for suxamethonium and 7.8 (1.2) micrograms kg-1 min-1 for mivacurium. There was a significant negative correlation between recovery to T5 and infusion rate for mivacurium and for suxamethonium. It was equally easy to titrate the infusion rate to the desired degree of block in each group. The recovery index (T25-T75) after the infusion stopped was similar in patients who received mivacurium and those who received suxamethonium.
Topics: Adolescent; Adult; Anesthesia Recovery Period; Female; Humans; Infusions, Intravenous; Injections, Intravenous; Intubation, Intratracheal; Isoquinolines; Male; Middle Aged; Mivacurium; Neuromuscular Junction; Neuromuscular Nondepolarizing Agents; Succinylcholine; Time Factors
PubMed: 2525044
DOI: 10.1093/bja/62.5.488 -
Animals : An Open Access Journal From... Nov 2023Palmitic (C16:0), α-linolenic acid (C18:3n-3 ), and propionate regulate bovine pyruvate carboxylase () and phosphoenolpyruvate carboxykinase () expression in vitro. The...
Effects of an Hourly Bolus Postruminal Infusion of Flaxseed Oil or Palm Oil on Circulating Fatty Acid Concentrations and Hepatic Expression of Pyruvate Carboxylase and Phosphoenolpyruvate Carboxykinase in Dairy Cattle.
Palmitic (C16:0), α-linolenic acid (C18:3n-3 ), and propionate regulate bovine pyruvate carboxylase () and phosphoenolpyruvate carboxykinase () expression in vitro. The objective of this experiment was to determine the impact of C16:0, C18:3n-3 , propionate, and acetate postruminal infusions on hepatic and expression. We hypothesized that circulating fatty acids alter hepatic and in lactating dairy cows. Acetate, propionate, palm oil, and flaxseed oil were supplied postruminally to lactating cows ( = 4) using two 4 × 4 Latin square studies. For Experiment 1, cows were infused on an hourly basis with either a bolus of propionate, acetate, or the combination of propionate and palm oil, or acetate and palm oil, and Experiment 2 was similar, but flaxseed oil replaced palm oil. Flaxseed infusions increased plasma concentration and the molar percent of C18:3n-3 and decreased C16:0 but did not affect or expression. Palm infusions did not affect blood metabolites or the hepatic expression of or . The lack of responses to short-chain fatty acid infusions and changes in circulating long-chain fatty acids in mature cattle are not suitable models to study the effects of α-linolenic acid and propionate on bovine and expression previously observed in vitro.
PubMed: 38003190
DOI: 10.3390/ani13223572 -
Applied Clinical Informatics Aug 2020Processes for delivery of high-risk infusions in pediatric intensive care units (PICUs) are complex. Standard concentration infusions (SCIs), smart-pumps, and electronic... (Observational Study)
Observational Study
BACKGROUND
Processes for delivery of high-risk infusions in pediatric intensive care units (PICUs) are complex. Standard concentration infusions (SCIs), smart-pumps, and electronic prescribing are recommended medication error reduction strategies. Implementation rates in Europe lag behind those in the United States. Since 2012, the PICU of an Irish tertiary pediatric hospital has been using a smart-pump SCI library, interfaced with electronic infusion orders (Philips ICCA). The incidence of infusion errors is unknown.
OBJECTIVES
To determine the frequency, severity, and distribution of smart-pump infusion errors in PICUs.
METHODS
Programmed infusions were directly observed at the bedside. Parameters were compared against medication orders and autodocumented infusion data. Identified deviations were categorized as medication errors or discrepancies. Error rates (%) were calculated as infusions with errors and errors per opportunities for error (OEs). Predefined definitions, multidisciplinary consensus and grading processes were employed.
RESULTS
A total of 1,023 infusions for 175 patients were directly observed over 27 days between February and September 2017. The drug library accommodated 96.5% of infusions. Compliance with the drug library was 98.9%. A total of 133 infusions had ≥1 error (13.0%); a further 58 (5.7%) had ≥1 discrepancy. From a total of 4,997 OEs, 153 errors (3.1%) and 107 discrepancies (2.1%) were observed. Undocumented bolus doses were most commonly identified ( = 81); this was the only deviation in 36.1% ( = 69) of infusions. Programming errors were rare (0.32% OE). Errors were minor, with just one requiring minimal intervention to prevent harm.
CONCLUSION
The error rates identified are low compared with similar studies, highlighting the benefits of smart-pumps and autodocumented infusion data in PICUs. A range of quality improvement opportunities has been identified.
Topics: Documentation; Electronic Prescribing; Humans; Infusion Pumps; Intensive Care Units, Pediatric; Medical Errors; Quality of Health Care
PubMed: 33027835
DOI: 10.1055/s-0040-1716527 -
Oncology (Williston Park, N.Y.) Oct 1998The treatment of advanced colorectal cancer has been evaluated in a series of randomized trials, including infusional and modulated 5-fluorouracil (5-FU), and three... (Review)
Review
The treatment of advanced colorectal cancer has been evaluated in a series of randomized trials, including infusional and modulated 5-fluorouracil (5-FU), and three meta-analyses encompassing trials of 5-FU plus leucovorin, continuous-infusion 5-FU, and intra-arterial fluoropyrimidines. A Southwest Oncology Group seven-arm phase II trial suggested that infusional 5-FU produced the most favorable toxicity spectrum and the longest survival, warranting further investigation in phase III trials. In a randomized phase III five-arm trial conducted by the Eastern Cooperative Oncology Group and the Cancer and Leukemia Group B, significant toxicity differences noted among the arms favored high-dose infusional 5-FU. In addition, the trial showed that 5-FU modulated by leucovorin or interferon was not more effective than 5-FU given as a 24-hour high-dose infusion weekly, and N-(phosphonacetyl)-L-aspartic acid did not enhance the activity of the weekly infusional 5-FU. Oral leucovorin provided no advantage over IV dosing. There was a significant difference in survival for patients with nonmeasurable disease (16.9 months) compared to those with measurable disease (12.6 months, P = .001). The Advanced Colorectal Cancer Meta-analysis Project demonstrated a response advantage for patients receiving 5-FU plus leucovorin (23%) compared to those receiving bolus 5-FU (11%, P = 10(-7); however, there was no survival advantage of 5-FU plus leucovorin over 5-FU alone (P = 0.57). The Meta-Analysis Group in Cancer showed that continuous-infusion 5-FU resulted in a statistically significantly higher response rate than bolus 5-FU (22% vs 14%, P = .0002). Overall survival also favored continuous-infusion 5-FU (P = .04). Continuous-infusion 5-FU was less toxic than bolus treatment. Data from six select randomized trials comparing hepatic intra-arterial infusion of FUDR to systemic therapy demonstrated a significant difference favoring intra-arterial therapy. Future directions for the treatment of advanced colorectal cancer include ongoing trials comparing low-dose vs high-dose infusional 5-FU, intra-arterial FUDR, leucovorin and dexamethasone vs systemic leucovorin plus 5-FU and proposed trials evaluating the dihydropyrimidine dehydrogenase inhibitor eniluracil plus oral 5-FU. Other drugs of interest include UFT, capecitabine, thymidylate synthase inhibitors, oxaliplatin, and irinotecan combinations.
Topics: Antimetabolites, Antineoplastic; Antineoplastic Combined Chemotherapy Protocols; Colorectal Neoplasms; Fluorouracil; Hepatic Artery; Humans; Infusions, Intra-Arterial; Infusions, Intravenous; Injections, Intravenous; Leucovorin; Meta-Analysis as Topic; Randomized Controlled Trials as Topic; Treatment Outcome
PubMed: 9830622
DOI: No ID Found -
Anesthesiology Feb 2024Remimazolam exhibits sedative properties by binding to γ-aminobutyric acid type A receptors. Remimazolam is administered as a bolus dose or continuous infusion, but has... (Clinical Trial)
Clinical Trial
BACKGROUND
Remimazolam exhibits sedative properties by binding to γ-aminobutyric acid type A receptors. Remimazolam is administered as a bolus dose or continuous infusion, but has not been studied using target-controlled infusion (TCI). The study quantified the relationship between the remimazolam concentration, Modified Observer's Assessment of Alertness and Sedation (MOAAS) score, and bispectral index (BIS) using TCI.
METHODS
The authors performed a three-period, crossover, dose-ranging clinical trial in 24 healthy volunteers using age and sex stratification. Data collected in the first period, where remimazolam was administered alone using a step-up and step-down TCI protocol, were used for this analysis. Remimazolam concentrations, MOAAS scores, and BIS values were collected at each step at steady state. Data were analyzed using nonlinear mixed-effects modeling methodology.
RESULTS
The relationship between remimazolam, BIS, and MOAAS differed between step-up and step-down infusions at similar remimazolam target concentrations. Tolerance, driven by remimazolam or CNS7054, significantly improved overall model fit (P < 0.01) for both BIS and MOAAS models. After 30 min of repeated bolus dosing, mimicking the regimen in the label for procedural sedation, the BIS and probability of MOAAS 2/3 were predicted to be 54 (95% prediction interval, 44 to 67) and 2% (95% prediction interval, 0 to 32%) versus 58 (95% prediction interval, 48 to 70) and 8% (95% prediction interval, 0 to 36%) in a model without and with tolerance, respectively. After 60 min of continuous infusion, mimicking the regimen in the label for general anesthesia, the BIS and probability of MOAAS 0 were predicted to be 40 (95% prediction interval, 33 to 50) and 87% (95% prediction interval, 18 to 100%) versus 50 (95% prediction interval, 41 to 60) and 59% (95% prediction interval, 6 to 99%) in a model without and with tolerance, respectively.
CONCLUSIONS
In this study, it was shown that remimazolam-induced sedation is prone to tolerance development, which is potentially mediated by the CNS7054 concentration. The clinical consequences are, however, limited in situations where remimazolam is titrated to effect.
Topics: Humans; Anesthesia, General; Benzodiazepines; Healthy Volunteers; Hypnotics and Sedatives; Infusions, Intravenous
PubMed: 37889844
DOI: 10.1097/ALN.0000000000004811 -
Anatolian Journal of Cardiology Aug 2020Early identification of viable myocardium in ischemic cardiomyopathy (ICM) patients is essential for early intervention and better clinical outcome. 99mTechnetium...
Does myocardial viability detection improve using a novel combined 99mTc sestamibi infusion and low dose dobutamine infusion in high risk ischemic cardiomyopathy patients?
OBJECTIVE
Early identification of viable myocardium in ischemic cardiomyopathy (ICM) patients is essential for early intervention and better clinical outcome. 99mTechnetium (99mTc) sestamibi gated myocardial perfusion imaging (gMPI) is a well-established technique for myocardial viability evaluation. Detection of potentially viable segments is a predictor of hibernating myocardium. ICM patients with hibernation have a better prognosis after revascularization. We used a novel infusion technique to determine better viability detection preoperatively in challenging situations. Like thallium, does prolonged availability of sestamibi in circulation with additional low dose dobutamine steady infusion (DS Inf) facilitate improved myocardial viability?
METHODS
A total of 58 ICM patients with infarct and left ventricular ejection fraction (LVEF) <45% underwent 99mTc sestamibi bolus injection followed by slow intravenous infusion single-photon emission computed tomography (SPECT) using a 2 day protocol. After acquiring the second set of 99mTc sestamibi infusion images, a third SPECT gMPI was performed during DS Inf.
RESULTS
A 17-segment myocardial model was used; 52 of 58 patients (548/986 segments) demonstrated perfusion defects (nonviable myocardium) on bolus study. Only 24 patients demonstrated viable segments by standard bolus imaging protocol. The slow MIBI infusion study demonstrated 158 viable segments (12 ICM patients), while combined infusion (99mTc sestamibi+DS Inf) exhibited an additional 6 patients with improved myocardial viability. Thus, 18 high risk patients benefited by this novel infusion technique to demonstrate viable myocardium on SPECT. There was a significantly higher sensitivity (p=0.05) and positive predictive value (p=0.01) in viability identification with the combined DS Inf technique. In dysfunctional segments, the rate of concordance for detecting viability between infusion and bolus techniques was 65%. Paired t test showed statistically significant improvement in viability detection with combined infusion compared to the bolus study (p=0.001).
CONCLUSION
This novel infusion technique was shown to be feasible and incremental in viability detection in ICM patients with severe left ventricular dysfunction. It is a robust tool to guide revascularization, in high risk ICM patients. This study also showed that patients with large transmural MI demonstrated no significant improvement in myocardial perfusion status using either protocol.
Topics: Adult; Aged; Cardiotonic Agents; Dobutamine; Drug Administration Schedule; Echocardiography; Female; Humans; Infusions, Intravenous; Male; Middle Aged; Myocardial Ischemia; Predictive Value of Tests; Radiopharmaceuticals; Technetium Tc 99m Sestamibi; Tomography, Emission-Computed, Single-Photon
PubMed: 32749255
DOI: 10.14744/AnatolJCardiol.2020.99148