Successful implementation of safe practice for adult intravenous push medication in a tertiary care hospital: determination of stability of four intravenous antibiotics in syringes.

In 2017, a severe shortage of infusion bags resulted in a paradigm change in medication administration practice from intermittent infusion to intravenous push. The Institute for Safe Medication Practices proposed safe practice guidelines for adult intravenous push medications. A different study showed that ready-to-administer medication prepared in the sterile area of a pharmacy reduces the risk of harm, nurses' time for medication administration and the cost of medications. Based on the recommendation of the Institute for Safe Medication Practices, we decided to conduct a pilot study on the implementation of sterile compounding and administration of intravenous push medication in adult patients admitted to the hospital. In the study, the stability of five intravenous push antibiotic syringes was also determined in the syringes.

Inibidor de C1 esterase derivado do plasma humano via intravenosa para o tratamento de crises de angioedema hereditário em pacientes com dois anos ou mais de idade / C1 esterase inhibitor derived from human plasma intravenously for the treatment of hereditary angioedema crises in patients with two or more years of age

INTRODUÇÃO: O angioedema hereditário (AEH) é uma doença genética ultrarrara, potencialmente fatal e subdiagnosticada. É uma imunodeficiência primária do sistema complemento, e foi classificado como um erro inato da imunidade em decorrência da deficiência de inibidor de C1 esterase (C1-INH), proteína que controla as vias de ativação do complemento. A alteração do C1-INH leva ao aumento da produção de bradicinina que, por sua vez, causa vasodilatação, aumento da permeabilidade dos vasos e extravasamento de plasma. A classificação mais atualizada do AEH agrupa os pacientes naqueles com deficiência do inibidor da C1-esterase (C1-INH), codificado pelo gene SERPING1 e naqueles C1-INH normal (anteriormente denominado de tipo III). Os pacientes com mutação do SERPING1 podem apresentar uma deficiência quantitativa do C1-INH (AEH tipo I) ou uma proteína anômala que resulta em deficiência funcional do C1-INH (tipo II). O diagnóstico é realizado através do exame clínico (anamnese, exame físico e quadro clínico) e laboratorial (dosagem de C4 e de C1-INH), além de teste genético (presença de mutação patogênica em SERPING1) para confirmação. O AEH não tem cura, porém há opções terapêuticas para a profilaxia e controle das crises agudas. Conforme o atual Protocolo Clínico e Diretrizes Terapêuticas (PCDT) de Angioedema associado a deficiência de C1 esterase (C1-INH), o tratamento das crises agudas é realizado em ambiente hospitalar, com uso de plasma fresco congelado, caso exista o risco de asfixia para o paciente. O plasma fresco congelado não foi testado em ensaios clínicos quanto à sua eficácia e segurança nas crises de AEH, e sua administração oferece não apenas a reposição do C1-INH, mas também os substratos nos quais ess

Low-Concentration Norepinephrine Infusion for Major Surgery: A Safety and Feasibility Pilot Randomized Controlled Trial.

BACKGROUND: Prevention of hypotension during the intra- and postoperative period is an important goal. Peripheral administration of low-concentration norepinephrine may be a safe and effective strategy to reduce the risk of hypotension. METHODS: We conducted a 2-center, randomized pilot feasibility trial, with a target of 60 adult patients undergoing major noncardiac surgery. We randomized patients to receive a peripheral low-concentration (10 µg/mL) norepinephrine or placebo (saline 0.9%) infusion. The study drug infusion was titrated to achieve a minimum systolic blood pressure target, preselected within 10% of baseline value and within the range limit 100 to 120 mm Hg during surgery and for up to 4 or 24 hours postoperatively. RESULTS: We achieved a high consent rate (84%), successful study drug administration throughout surgery (98% of patients) and absence of unblinding. There were no important study drug-related adverse events. The average intraoperative systolic blood pressure was 120 ± 12.6 mm Hg in the norepinephrine group and 115 ± 14.9 mm Hg in the placebo group. The mean difference between the intraoperative systolic blood pressure achieved less the preselected minimum systolic blood pressure target was 10.0 ± 12.7 mm Hg in the norepinephrine group and 2.9 ± 14.7 mm Hg in the placebo group; difference in means, 7.1 (95% confidence interval, 0.2-14.0) mm Hg. CONCLUSIONS: A future large trial evaluating the effectiveness and safety of peripheral administration of low-concentration norepinephrine during the perioperative period is feasible, and likely to achieve a minimum systolic blood pressure threshold.

Comparison of a metronome-guided prehospital medication infusion technique with standard calculation: a simulated randomized, controlled, cross-over study.

BACKGROUND: Limited research regarding administration of timed medication infusions in the prehospital environment has identified wide variability with accuracy, timing, and overall feasibility. This study was a quality improvement project that utilized a randomized, controlled, crossover study design to compare two different educational techniques for medication infusion administration. We hypothesized that the use of a metronome-based technique would decrease medication dosage errors and reduce time to administration for intravenous medication infusions. METHODS: Forty-two nationally registered paramedics were randomized to either a metronome-based technique versus a standard stopwatch-based technique. Each subject served as a control. Subjects were asked to establish an infusion of amiodarone at a dose of 150 mg administered over 10 min, simulating treatment of a hemodynamically stable patient with sustained monomorphic ventricular tachycardia. Descriptive statistics and a repeated measures mixed linear regression model were used for data analysis. RESULTS: When compared to a standard stopwatch-based technique, a metronome-based technique was associated with faster time to goal (median 34 s [IQR, 22-54] vs 50 s; [IQR 38-61 s], P = 0.006) and fewer mid-infusion adjustments. Ease of use was reported to be significantly higher for the metronome group (median ranking 5, IQR 4-5) compared to the standard group (median ranking 2, IQR 2-3; P < 0.001). CONCLUSIONS: Knowledge regarding a metronome technique may help EMS clinicians provide safe and effective IV infusions. Such a technique may be beneficial for learners and educators alike.

Comparison of the effect of continuous intravenous infusion of sodium valproate and midazolam on management of status epilepticus in children.

BACKGROUND AND OBJECTIVES: Status epilepticus as a pediatric emergency requires rapid seizure control in order to prevent subsequent disabilities. Therefore, the present study was conducted to compare the efficacy and side effects of continuous intravenous infusion of sodium valproate versus midazolam as a third-line treatment of status epilepticus in children. METHODOLOGY: This randomized clinical trial study included all children with convulsive and non-convulsive status epilepticus admitted to the pediatric intensive care unit (PICU) of the Bu-Ali Sina Hospital in Sari City (Mazandaran Province, Iran) who had not responded to first-line treatment with diazepam and second-line treatment with phenytoin or phenobarbital. They were consequently treated with continuous intravenous infusion of sodium valproate or midazolam to control persistent seizures. RESULTS: The study comprised 70 patients who were randomly assigned to two equal groups of sodium valproate or midazolam treatment. The mean age of patients in group A (sodium valproate) and group B (midazolam) was 3.97 ± 3.33 and 3.84 ± 2.93 years, respectively. In the present study, the most common etiology of status epilepticus was remote symptomatic, accounting for 35% of cases in the two groups. Sodium valproate was effective in controlling status epilepticus in 91.4% of patients, while midazolam was found to be effective in 85.7% of patients (p > 0.05). Patients who received sodium valproate had shorter seizure duration after administration of the drug compared to those who received midazolam (p = 0.01). Eight patients in the midazolam group and two patients in the sodium valproate group were intubated (p = 0.023). The mean duration of stay in the PICU was 3.2 ± 1.4 and 5.6 ± 2.8 days in groups A and B, respectively, showing a significant difference (p = 0.001). CONCLUSION: According to our findings, intravenous infusion of sodium valproate can be used as an effective and relatively safe treatment in children with all types of status epilepticus, especially in challenging situations such as lack of intensive care units or respiratory problems.

Pharmacokinetic Properties of S-oxiracetam After Single and Multiple Intravenous Infusions in Healthy Volunteers.

BACKGROUND AND OBJECTIVES: As a chiral drug, oxiracetam (ORT) can exist in two different isomeric forms: S-oxiracetam (S-ORT) and R-oxiracetam (R-ORT). S-ORT has emerged as a promising nootropic drug with the potential to treat brain injury and the resulting loss of neural function, memory and mental impairment as assessed by studies in various animal models. However, limited data are available on the pharmacokinetics of S-ORT in humans, so the present study was designed to evaluate the safety and pharmacokinetic profile of S-ORT in healthy volunteers. METHODS: In part 1, subjects were intravenously administered single ascending dose (2.0, 4.0 and 8.0 g) S-ORT. In part 2, subjects were treated at a single intravenous infusion dose of 3.0 g S-ORT or 6.0 g racemic ORT using a two-sequence, two-period crossover design. In part 3, subjects were intravenously injected with 4.0 g S-ORT once a day for 7 days. Blood and urine samples were collected to evaluate the pharmacokinetic parameters and urine excretion rate. The safety profile of the drug was also evaluated throughout the study. RESULTS: Fifty-two subjects (30 in part 1, 12 in part 2, 10 in part 3) completed the study; only one subject displayed a mild adverse event, which possibly was treatment related, and no serious adverse event occurred. In part 1 for a single dose of 2.0, 4.0 and 8.0 g, the maximum concentration (Cmax) values were 111.28 ± 18.99, 230.76 ± 29.16 and 352.67 ± 42.94 µg/ml, respectively; the values of area under the plasma concentration-time curve (AUC) from time zero to the time of last quantifiable concentration (AUC0-t) were 267.09 ± 59.66, 524.50  ± 72.87 and 822.68 ± 95.21 µg·h/ml, respectively; the AUC from 0 h to infinity (AUC0-∞) values were 274.72 ± 61.65, 536.06 ± 78.13 and 832.07 ± 96.91 µg·h/ml, respectively. The urine excretion rate of the unchanged drug was approximately 60%. After consecutive administration of S-ORT for 7 days, the accumulation index was 1.05 ± 0.08. The plasma drug concentration-time curves for both S-ORT and R-oxiracetam (R-ORT) were almost identical. CONCLUSIONS: S-ORT was well tolerated, and no serious adverse events occurred in 2.0, 4.0 and 8.0 g in single- and 4.0 g in multiple-dose studies. S-ORT showed dose linearity with increasing doses and no drug accumulation after 7 days of continuous administration was observed.

Dose individualization of intravenous busulfan in pediatric patients undergoing bone marrow transplantation: impact and in vitro evaluation of infusion lag-time.

OBJECTIVES: To apply therapeutic drug monitoring and dose-individualization of intravenous Busulfan to paediatric patients and evaluate the impact of syringe-pump induced Busulfan infusion lag-time after in vitro estimation. METHODS: 76 children and adolescents were administered 2 h intravenous Busulfan infusion every 6 h (16 doses). Busulfan plasma levels, withdrawn by an optimized sampling scheme and measured by a validated HPLC-PDA method, were used to estimate basic PK parameters, AUC, Cmax, kel, t1/2, applying Non-Compartmental Analysis. In vivo infusion lag-time was simulated in vitro and used to evaluate its impact on AUC estimation. KEY FINDINGS: Mean (%CV) Busulfan AUC, Cmax, clearance and t1/2 for pediatric population were found 962.3 µm × min (33.1), 0.95 mg/L (41.4), 0.27 L/h/kg (33.3), 2.2 h (27.8), respectively. TDM applied to 76 children revealed 6 (7.9%) being above and 25 (32.9%) below therapeutic-range (AUC: 900-1350 µm × min). After dose correction, all patients were measured below toxic levels (AUC < 1500 µm × min), no patient below 900 µm × min. Incorporation of infusion lag-time revealed lower AUCs with 17.1% more patients and 23.1% more younger patients, with body weight <16 kg, being below the therapeutic-range. CONCLUSIONS: TDM, applied successfully to 76 children, confirmed the need for Busulfan dose-individualization in paediatric patients. Infusion lag-time was proved clinically significant for younger, low body-weight patients and those close to the lower therapeutic-range limit.

Off-label use of plastic syringes with silicone oil for intravenous infusion bags of antibodies.

The formation of particulates in post-manufacture biopharmaceuticals continues to be a major concern in medical treatment. This study was designed to evaluate the content of micro-sized particles using flow imaging of antibodies in intravenous infusion bags. Intravenous immunoglobulin (IVIG) and Avastin® were selected as model drugs and plastic syringes with and without silicone oil (SO) were used to transfer the drugs into the bags (0.9% saline or 5% dextrose). Antibodies exposed to SO had significantly increased levels of microparticles in both diluents, suggesting SO accelerates particle formation, especially at a higher antibody concentration. Even before the drop stress, their count exceeded the USP guideline. Dropping the bags in the presence of SO produced larger microparticles. Meanwhile, air bubbles were retained longer in saline suggesting more protein film formation on its air-water interface. Overall, both drugs were conformationally stable and produced less particles in dextrose than in saline.

Study of blood glucose and insulin infusion rate in real-time in diabetic rats using an artificial pancreas system.

Artificial pancreas system (APS) is an emerging new treatment for type 1 diabetes mellitus. The aim of this study was to develop a rat APS as a research tool and demonstrate its application. We established a rat APS using Medtronic Minimed Pump 722, Medtronic Enlite sensor, and the open artificial pancreas system as a controller. We tested different dilutions of Humalog (100 units/ml) in saline ranged from 1:3 to 1:20 and determined that 1:7 dilution works well for rats with ~500g bodyweight. Blood glucose levels (BGL) of diabetic rats fed with chow diet (58% carbohydrate) whose BGL was managed by the closed-loop APS for the total duration of 207h were in euglycemic range (70-180 mg/dl) for 94.5% of the time with 2.1% and 3.4% for hyperglycemia (>180mg/dl) and hypoglycemia (<70 mg/dl), respectively. Diabetic rats fed with Sucrose pellets (94.8% carbohydrate) for the experimental duration of 175h were in euglycemic range for 61% of the time with 35% and 4% for hyperglycemia and hypoglycemia, respectively. Heathy rats fed with chow diet showed almost a straight line of BGL ~ 95 mg/dl (average 94.8 mg/dl) during the entire experimental period (281h), which was minimally altered by food intake. In the healthy rats, feeding sucrose pellets caused greater range of BGL in high and low levels but still within euglycemic range (99.9%). Next, to study how healthy and diabetic rats handle supra-physiological concentrations of glucose, we intraperitoneally injected various amounts of 50% dextrose (2, 3, 4g/kg) and monitored BGL. Duration of hyperglycemia after injection of 50% dextrose at all three different concentrations was significantly greater for healthy rats than diabetic rats, suggesting that insulin infusion by APS was superior in reducing BGL as compared to natural insulin released from pancreatic ß-cells. Ex vivo studies showed that islets isolated from diabetic rats were almost completely devoid of pancreatic ß-cells but with intact α-cells as expected. Lipid droplet deposition in the liver of diabetic rats was significantly lower with higher levels of triacylglyceride in the blood as compared to those of healthy rats, suggesting lipid metabolism was altered in diabetic rats. However, glycogen storage in the liver determined by Periodic acid-Schiff staining was not altered in diabetic rats as compared to healthy rats. A rat APS may be used as a powerful tool not only to study alterations of glucose and insulin homeostasis in real-time caused by diet, exercise, hormones, or antidiabetic agents, but also to test mathematical and engineering models of blood glucose prediction or new algorithms for closed-loop APS.

Efficacy and safety associated with the infusion speed of intravenous immunoglobulin for the treatment of Kawasaki disease: a randomized controlled trial.

BACKGROUND: High-dose intravenous immunoglobulin (IVIG) is the mainstay of treatment for Kawasaki disease (KD). Usually, 2 g/kg of IVIG is administered over 10-24 h, depending on the institution or physician, but the association between infusion speed and effectiveness has not been reported. In this study, we evaluated the differences in efficacy and safety between two different IVIG administration speeds. METHODS: This was a multicenter, unblinded, randomized controlled study. Patients newly diagnosed with KD were randomized into two groups: one who received IVIG over 12 h (12H group, double speed), and one that received IVIG over 24 h (24H group, reference speed). The endpoints included the duration of fever, incidence of coronary artery abnormalities (CAAs) and of adverse events. Laboratory data were evaluated before and after IVIG administration. RESULTS: A total of 39 patients were enrolled. There was no difference between groups in fever duration after the initiation of IVIG (21 h vs. 21.5 h, p = 0.325), and no patient experienced CAAs. Two adverse events were observed in the 12H group (elevation of aspartate aminotransferase and vomiting), however no severe adverse events requiring treatments or extension of hospital stay were observed in either group. After initial IVIG administration, the change ratio of inflammatory markers, such as white blood cell counts, neutrophils, C-reactive protein, and albumin, did not show significant differences between the two groups. On the other hand, a greater increase of serum immunoglobulin G from its baseline level was observed in the 24H group compared to the 12H group (3037 ± 648 mg/dl vs. 2414 ± 248 mg/dl, p < 0.01). CONCLUSION: The efficacy and safety of IVIG administered over 12 h (double speed) were similar to those administered over 24 h (reference speed). TRIAL REGISTRATION: University Hospital Medical Information Network ( UMIN000014665 ). Registered 27 July 2014 - Prospectively registered, https://upload.umin.ac.jp/cgi-open-bin/ctr/ctr_view.cgi?recptno=R000017058.

Early diuretic strategies and the association with In-hospital and Post-discharge outcomes in acute heart failure.

BACKGROUND: Decongestion is a primary goal during hospitalizations for decompensated heart failure (HF). However, data surrounding the preferred route and strategy of diuretic administration are limited with varying results in prior studies. METHODS: This is a retrospective analysis using patients from ASCEND-HF with a stable diuretic strategy in the first 24 hours following randomization. Patients were divided into three groups: intravenous (IV) continuous, IV bolus and oral strategy. Baseline characteristics, in-hospital outcomes, 30-day composite cardiovascular mortality or HF rehospitalization and 180-day all-cause mortality were compared across groups. Inverse propensity weighted modeling was used for adjustment. RESULTS: Among 5,738 patients with a stable diuretic regimen in the first 24 hours (80% of overall ASCEND trial), 3,944 (68.7%) patients received IV intermittent bolus administration of diuretics, 799 (13.9%) patients received IV continuous therapy and 995 (17.3%) patients with oral administration. Patients in the IV continuous group had a higher baseline creatinine (IV continuous 1.4 [1.1-1.7]; intermittent bolus 1.2 [1.0-1.6]; oral 1.2 [1.0-1.4] mg/dL; P <0.001) and high NTproBNP (IV continuous 5,216 [2,599-11,603]; intermittent bolus 4,944 [2,339-9,970]; oral 3,344 [1,570-7,077] pg/mL; P <0.001). There was no difference between IV continuous and intermittent bolus group in weight change, total urine output and change in renal function till 10 days/discharge (adjusted P >0.05 for all). There was no difference in 30 day mortality and HF readmission (adjusted OR 1.08 [95%CI: 0.74, 1.57]; P = 0.701) and 180 days mortality (adjusted OR 1.04 [95%CI: 0.75, 1.43]; P = 0.832). CONCLUSION: In a large cohort of patients with decompensated HF, there were no significant differences in diuretic-related in-hospital, or post-discharge outcomes between IV continuous and intermittent bolus administration. Tailoring appropriate diuretic strategy to different states of acute HF and congestion phenotypes needs to be further investigated.

A surgical method for continuous intraportal infusion of gut microbial metabolites in mice.

Gut microbe-derived metabolites influence human physiology and disease. However, establishing mechanistic links between gut microbial metabolites and disease pathogenesis in animal models remains challenging. The major route of absorption for microbe-derived small molecules is venous drainage via the portal vein to the liver. In the event of presystemic hepatic metabolism, the route of metabolite administration becomes critical. To our knowledge, we describe here a novel portal vein cannulation technique using a s.c. implanted osmotic pump to achieve continuous portal vein infusion in mice. We first administered the microbial metabolite trimethylamine (TMA) over 4 weeks, during which increased peripheral plasma levels of TMA and its host liver-derived cometabolite, trimethylamine-N-oxide, were observed when compared with a vehicle control. Next, 4-hydroxyphenylacetic acid (4-HPAA), a microbial metabolite that undergoes extensive presystemic hepatic metabolism, was administered intraportally to examine effects on hepatic gene expression. As expected, hepatic levels of 4-HPAA were elevated when compared with the control group while peripheral plasma 4-HPAA levels remained the same. Moreover, significant changes in the hepatic transcriptome were revealed by an unbiased RNA-Seq approach. Collectively, to our knowledge this work describes a novel method for administering gut microbe-derived metabolites via the portal vein, mimicking their physiologic delivery in vivo.

Outpatient therapy with piperacillin/tazobactam using elastomeric pumps in patients with Pseudomonas aeruginosa infection.

The aim of this study was to evaluate the efficacy and safety of outpatient antimicrobial therapy with piperacillin-tazobactam in continuous infusion using elastomeric pumps and to evaluate the economic impact compared with conventional hospital treatment in patients with Pseudomonas aeruginosa (PA) infections. This is an observational study. Patients with PA infection treated with continuous piperacillin-tazobactam infusion using elastomeric pumps in our hospital between January 2015 and December 2017 were included. Primary outcomes were mortality during antibiotic treatment and mortality at 30 days. Secondary outcomes were reinfection or relapse at 30 days and clinical cure rate. The cost of each episode was compared with theoretical cost of the same treatment using conventional hospitalization. 35 patients were included. One patient (2.9%) died during the treatment. Overall 30-day mortality was 5.7%. No death was related to infection by PA. One patient (2.9%) had a reinfection at 30 days. Cure was achieved in 93% of patients at the end of treatment. There were no severe complications related to elastomeric pumps. Treatment cost with outpatient antimicrobial therapy was 67% lower than theoretical cost with conventional hospital treatment. Oupatient antimicrobial therapy with piperacillin-tazobactam in continuous infusion using elastomeric pumps in patients with PA infections is safe and effective with lower costs.